Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells

PubMed Central

Osawa, T; Davies, D; Hartley, J A

2011-01-01

DNA interstrand cross-links (ICLs) are critical cytotoxic lesions produced by cancer chemotherapeutic agents such as the nitrogen mustards and platinum drugs; however, the exact mechanism of ICL-induced cell death is unclear. Here, we show a novel mechanism of p53-independent apoptotic cell death involving prolonged cell-cycle (G2) arrest, ICL repair involving HR, transient mitosis, incomplete cytokinesis, and gross chromosomal abnormalities resulting from ICLs in mammalian cells. This characteristic ‘giant' cell death, observed by using time-lapse video microscopy, was reduced in ICL repair ERCC1- and XRCC3-deficient cells. Collectively, the results illustrate the coordination of ICL-induced cellular responses, including cell-cycle arrest, DNA damage repair, and cell death. PMID:21814285

DISENTANGLING THE ICL WITH THE CHEFs: ABELL 2744 AS A CASE STUDY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiménez-Teja, Y.; Dupke, R., E-mail: yojite@iaa.es

Measurements of the intracluster light (ICL) are still prone to methodological ambiguities, and there are multiple techniques in the literature to address them, mostly based on the binding energy, the local density distribution, or the surface brightness. A common issue with these methods is the a priori assumption of a number of hypotheses on either the ICL morphology, its surface brightness level, or some properties of the brightest cluster galaxy (BCG). The discrepancy in the results is high, and numerical simulations just place a boundary on the ICL fraction in present-day galaxy clusters in the range 10%–50%. We developed amore » new algorithm based on the Chebyshev–Fourier functions to estimate the ICL fraction without relying on any a priori assumption about the physical or geometrical characteristics of the ICL. We are able to not only disentangle the ICL from the galactic luminosity but mark out the limits of the BCG from the ICL in a natural way. We test our technique with the recently released data of the cluster Abell 2744, observed by the Frontier Fields program. The complexity of this multiple merging cluster system and the formidable depth of these images make it a challenging test case to prove the efficiency of our algorithm. We found a final ICL fraction of 19.17 ± 2.87%, which is very consistent with numerical simulations.« less

Intracluster light at the Frontier - II. The Frontier Fields Clusters

NASA Astrophysics Data System (ADS)

Montes, Mireia; Trujillo, Ignacio

2018-02-01

Multiwavelength deep observations are a key tool to understand the origin of the diffuse light in clusters of galaxies: the intracluster light (ICL). For this reason, we take advantage of the Hubble Frontier Fields (HFF) survey to investigate the properties of the stellar populations of the ICL of its six massive intermediate redshift (0.3 < z < 0.6) clusters. We carry on this analysis down to a radial distance of ˜120 kpc from the brightest cluster galaxy. We found that the average metallicity of the ICL is [Fe/H]ICL ˜ -0.5, compatible with the value of the outskirts of the Milky Way. The mean stellar ages of the ICL are between 2 and 6 Gyr younger than the most massive galaxies of the clusters. Those results suggest that the ICL of these massive (>1015 M⊙) clusters is formed by the stripping of MW-like objects that have been accreted at z < 1, in agreement with current simulations. We do not find any significant increase in the fraction of light of the ICL with cosmic time, although the redshift range explored is narrow to derive any strong conclusion. When exploring the slope of the stellar mass density profile, we found that the ICL of the HFF clusters follows the shape of their underlying dark matter haloes, in agreement with the idea that the ICL is the result of the stripping of galaxies at recent times.

The Fanconi anemia pathway and ICL repair: implications for cancer therapy

PubMed Central

Wang, Lily C; Gautier, Jean

2011-01-01

Fanconi anemia (FA) is an inherited disease caused by mutations in at least 13 genes and characterized by genomic instability. In addition to displaying strikingly heterogenous clinical phenotypes, FA patients are exquisitely sensitive to treatments with crosslinking agents that create interstrand crosslinks (ICL). In contrast to bacteria and yeast, in which ICLs are repaired through replication-dependent and –independent mechanisms, it is thought that ICLs are repaired primarily during DNA replication in vertebrates (Moldovan and D’Andrea, 2009). However, recent data indicate that replication-independent ICL repair also operates in vertebrates. While the precise role of the FA pathway in ICL repair remains elusive, increasing evidence suggests that FA proteins function at different steps in the sensing, recognition and processing of ICLs, as well as in signaling from these very toxic lesions, which can be generated by a wide variety of cancer chemotherapeutic drugs. Here, we discuss some of the recent findings that have shed light on the role of the FA pathway in ICL repair with special emphasis on the implications of these findings for cancer therapy since disruption of FA genes have been associated with cancer predisposition. PMID:20807115

Effects of V4c-ICL Implantation on Myopic Patients' Vision-Related Daily Activities

PubMed Central

Linghu, Shaorong; Pan, Le; Shi, Rong

2016-01-01

The new type implantable Collamer lens with a central hole (V4c-ICL) is widely used to treat myopia. However, halos occur in some patients after surgery. The aim is to evaluate the effect of V4c-ICL implantation on vision-related daily activities. This retrospective study included 42 patients. Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), intraocular pressure (IOP), endothelial cell density (ECD), and vault were recorded and vision-related daily activities were evaluated at 3 months after operation. The average spherical equivalent was −0.12 ± 0.33 D at 3 months after operation. UCVA equal to or better than preoperative BCVA occurred in 98% of eyes. The average BCVA at 3 months after operation was −0.03 ± 0.07 LogMAR, which was significantly better than preoperative BCVA (0.08 ± 0.10 LogMAR) (P = 0.029). Apart from one patient (2.4%) who had difficulty reading computer screens, all patients had satisfactory or very satisfactory results. During the early postoperation, halos occurred in 23 patients (54.8%). However there were no significant differences in the scores of visual functions between patients with and without halos (P > 0.05). Patients were very satisfied with their vision-related daily activities at 3 months after operation. The central hole of V4c-ICL does not affect patients' vision-related daily activities. PMID:27965890

Unique Dynamic Properties of DNA Duplexes Containing Interstrand Crosslinks†

PubMed Central

Friedman, Joshua I.; Jiang, Yu Lin; Miller, Paul S.; Stivers, James T.

2010-01-01

Bifunctional DNA alkylating agents form a diverse assortment of covalent DNA interstrand crosslinked (ICL) structures that are potent cytotoxins. Since it is implausible that cells could possess distinct DNA repair systems for each individual ICL, it is believed that common structural and dynamic features of ICL damage are recognized, rather than specific structural characteristics of each cross-linking agent. Investigation of the structural and dynamic properties of ICLs that might be important for recognition has been complicated by heterogeneous incorporation of these lesions into DNA. To address this problem we have synthesized and characterized several homogenous ICL-DNAs containing site–specific staggered N4-cytosine-ethyl-N4-cytosine crosslinks. Staggered crosslinks were introduced in two ways: in a manner that preserves the overall structure of B-form duplex DNA, and in a manner that highly distorts the DNA structure, with the goal of understanding how structural and dynamic properties of diverse ICL duplexes might flag these sites for repair. Measurements of base pair opening dynamics in the B-form ICL duplex by 1H NMR linewidth or imino proton solvent exchange showed that the guanine base opposite to the crosslinked cytosine opened at least an order of magnitude more slowly than when in a control matched normal duplex. To a lesser degree, the B-form ICL also induced a decrease in base pair opening dynamics that extended from the site of the crosslink to adjacent base pairs. In contrast, the non-B-form ICL showed extensive conformational dynamics at the site of the cross link, which extended over the entire DNA sequence. Since DNA duplexes containing the B-form and non-B-form ICL crosslinks have both been shown to be incised when incubated in mammalian whole cell extracts, while a matched normal duplex is not, we conclude that intrinsic DNA dynamics is not a requirement for specific damage incision of these ICLs. Instead, we propose a general model where destabilized ICL-duplexes serve to energetically facilitate binding of DNA repair factors that must induce bubbles or other distortions in the duplex. However, the essential requirement for incision is an immobile Y-junction where the repair factors are stably bound at the site of the ICL, and the two DNA strands are unpaired. PMID:21174443

Metabolic adaptation via regulated enzyme degradation in the pathogenic yeast Candida albicans.

PubMed

Ting, S Y; Ishola, O A; Ahmed, M A; Tabana, Y M; Dahham, S; Agha, M T; Musa, S F; Muhammed, R; Than, L T L; Sandai, D

2017-03-01

The virulence of Candida albicans is dependent upon fitness attributes as well as virulence factors. These attributes include robust stress responses and metabolic flexibility. The assimilation of carbon sources is important for growth and essential for the establishment of infections by C. albicans. Previous studies showed that the C. albicans ICL1 genes, which encode the glyoxylate cycle enzymes isocitratelyase are required for growth on non-fermentable carbon sources such as lactate and oleic acid and were repressed by 2% glucose. In contrast to S. cerevsiae, the enzyme CaIcl1 was not destabilised by glucose, resulting with its metabolite remaining at high levels. Further glucose addition has caused CaIcl1 to lose its signal and mechanisms that trigger destabilization in response to glucose. Another purpose of this study was to test the stability of the Icl1 enzyme in response to the dietary sugars, fructose, and galactose. In the present study, the ICL1 mRNAs expression was quantified using Quantitative Real Time PCR, whereby the stability of protein was measured and quantified using Western blot and phosphoimager, and the replacing and cloning of ICL1 ORF by gene recombination and ubiquitin binding was conducted via co-immuno-precipitation. Following an analogous experimental approach, the analysis was repeated using S. cerevisiaeas a control. Both galactose and fructose were found to trigger the degradation of the ICL1 transcript in C. albicans. The Icl1 enzyme was stable following galactose addition but was degraded in response to fructose. C. albicans Icl1 (CaIcl1) was also subjected to fructose-accelerated degradation when expressed in S. cerevisiae, indicating that, although it lacks a ubiquitination site, CaIcl1 is sensitive to fructose-accelerated protein degradation. The addition of an ubiquitination site to CaIcl1 resulted in this enzyme becoming sensitive to galactose-accelerated degradation and increases its rate of degradation in the presence of fructose. It can be concluded that ubiquitin-independent pathways of fructose-accelerated enzyme degradation exist in C. albicans. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Visualizing Inhibition of Nucleosome Mobility and Transcription by Cisplatin-DNA Interstrand Crosslinks in Live Mammalian Cells

PubMed Central

Zhu, Guangyu; Song, Lina; Lippard, Stephen J.

2013-01-01

Cisplatin is a widely used anticancer drug that acts by binding DNA and causing the formation of intrastrand and interstrand (ICL) cross-links, but the precise downstream effects of the latter damage are not well understood. In this study, we investigated the influence of cisplatin ICLs on synthetic nucleosomes that were platinated in a site-specific manner in vitro and on gene transcription in live mammalian cells. Nucleosome core particles (NCPs) that we constructed contained site-specific cisplatin 5′-d(G*pC)/5′-d(G*pC) ICLs, where the asterisk denotes the platinated nucleoside, to examine the influence of platinum lesions on the dynamic behavior of nucleosomes in solution. A cisplatin ICL, but not a 1,2-d(GpG) cross-link, significantly inhibited ATP-independent histone octamer-DNA sliding. We also used a novel linearization-recircularization strategy described here to synthesize mammalian expression vectors containing site-specific cisplatin ICLs. Plasmid vectors were tested in live mammalian cellsto study the transcription inhibition effects of cisplatin ICLs in the context of two different repair backgrounds. Cisplatin ICLs inhibit transcription as effectively as 1,2-d(GpG) cross-links. We determined that nucleotide excision repair plays a key role in the removal of cisplatin ICLs, acting in a replication-independent fashion. We also found that loss of mismatch repair function dramatically attenuatesthe transcription inhibition effects by cisplatin ICLs but not 1,2-d(GpG) intrastrand cross-links. Our results revealed the unique properties of cisplatin ICLs on nucleosome mobility and on transcription, and they defined how these adducts act in a manner completely different from that used for cisplatin 1,2-d(GpG) cross-links. These new findings provide direct support for a role of ICLs in the pharmacological activities of cisplatin, despite the lower frequency of their formation. PMID:23695549

Identification of Ser153 in ICL2 of the gonadotropin-releasing hormone (GnRH) receptor as a phosphorylation-independent site for inhibition of Gq coupling.

PubMed

Shacham, Sharon; Cheifetz, Maya N; Fridkin, Mati; Pawson, Adam J; Millar, Robert P; Naor, Zvi

2005-08-12

Type I gonadotropin-releasing hormone (GnRH) receptor (GnRHR) is unique among mammalian G-protein-coupled receptors (GPCRs) in lacking a C-terminal tail, which is involved in desensitization in GPCRs. Therefore, we searched for inhibitory sites in the intracellular loops (ICLs) of the GnRHR. Synthetic peptides corresponding to the three ICLs were inserted into permeabilized alphaT3-1 gonadotrope cells, and GnRH-induced inositol phosphate (InsP) formation was determined. GnRH-induced InsP production was potentiated by ICL2 > ICL3 but not by the ICL1 peptides, suggesting they are acting as decoy peptides. We examined the effects of six peptides in which only one of the Ser or Thr residues was substituted with Ala or Glu. Only substitution of Ser153 with Ala or Glu ablated the potentiating effect upon GnRH-induced InsP elevation. ERK activation was enhanced, and the rate of GnRH-induced InsP formation was about 6.5-fold higher in the first 10 min in COS-1 cells that were transfected with mutants of the GnRHR in which the ICL2 Ser/Thr residues (Ser151, Ser153, and Thr142) or only Ser153 was mutated to Ala as compared with the wild type GnRHR. The data indicate that ICL2 harbors an inhibitory domain, such that exogenous ICL2 peptide serves as a decoy for the inhibitory site (Ser153) of the GnRHR, thus enabling further activation. GnRH does not induce receptor phosphorylation in alphaT3-1 cells. Because the phosphomimetic ICL2-S153E peptide did not mimic the stimulatory effect of the ICL2 peptide, the inhibitory effect of Ser153 operates through a phosphorylation-independent mechanism.

Crystalline lens changes in porcine eyes with implanted phakic IOL (ICL) with a central hole

PubMed Central

Shimizu, Kimiya; Fujisawa, Kunitoshi; Uga, Shigekazu; Nagano, Koichi; Murakami, Yuuki

2008-01-01

Background We calculated the smallest diameter of a hole in the center of the optic at which the optical character of a phakic IOL (ICL) may be maintained. The changes induced in the aqueous humor dynamics and the pathology of cataract development with such a hole were investigated. Methods A simulation was performed using ZEMAX software to calculate the hole diameter that makes possible the maintenance of a stable optical character of a phakic IOL. After a hole of calculated diameter was trepanned in the center of the optic of the ICL, the latter was implanted into one eye of a 5-month-old minipig, and an unperforated ICL into the other. The postoperative course was observed for 3 months. Then, Evans blue was injected into the vitreous body under general anesthesia to stain the anterior capsule of the crystalline lens. Within 30 min, the eye was enucleated and the tissues removed were fixed. Results The MTF of the perforated ICL (hole diameter, 1.0 mm) in the center of the optic resembled that of the unperforated ICL. In all cases with non-perforated ICLs, subcapsular turbidity developed, but no staining caused by EB was observed in the anterior capsule. On the other hand, the anterior capsules of the eyes fitted with ICLs with a 1.0-mm hole were stained, but exhibited no turbidity. Conclusion An ICL with a central hole of diameter 1.0 mm in the optic is similar to an unperforated ICL. The size of the hole influenced the aqueous humor dynamics and increased the aqueous humor perfusion volume over the entire anterior surface of the crystalline lens. The possibility of preventing cataracts was therefore suggested. PMID:18299877

Lost but not forgotten: intracluster light in galaxy groups and clusters

NASA Astrophysics Data System (ADS)

DeMaio, Tahlia; Gonzalez, Anthony H.; Zabludoff, Ann; Zaritsky, Dennis; Connor, Thomas; Donahue, Megan; Mulchaey, John S.

2018-03-01

With Hubble Space Telescope imaging, we investigate the progenitor population and formation mechanisms of the intracluster light (ICL) for 23 galaxy groups and clusters at 0.29 ≤ z ≤ 0.89. The colour gradients of the BCG+ICL become bluer with increasing radius out to 53-100 kpc for all but one system, suggesting that violent relaxation after major mergers with the BCG cannot be the dominant source of ICL. The BCG+ICL luminosities and stellar masses are too large for the ICL stars to come from the dissolution of dwarf galaxies alone, given the observed evolution of the faint end of the cluster galaxy luminosity function, implying instead that the ICL grows from the stripping of more massive galaxies. Using the colours of cluster members from the CLASH high-mass sample, we place conservative lower limits on the luminosities of galaxies from which the ICL at r < 100 kpc could originate via stripping. We find that the ICL at 100 kpc has a colour similar to a 1010.0 M⊙ galaxy and that 75 per cent of the total BCG+ICL luminosity at r < 100 kpc is consistent with originating in galaxies with L > 0.2 L* (log(M★ [M⊙])>10.4), assuming conservatively that these galaxies are completely disrupted. We conclude that the tidal stripping of massive galaxies is the likely source of the intracluster light from 10 to 100 kpc for galaxy groups and clusters.

Recruitment and positioning determine the specific role of the XPF-ERCC1 endonuclease in interstrand crosslink repair.

PubMed

Klein Douwel, Daisy; Hoogenboom, Wouter S; Boonen, Rick Acm; Knipscheer, Puck

2017-07-14

XPF-ERCC1 is a structure-specific endonuclease pivotal for several DNA repair pathways and, when mutated, can cause multiple diseases. Although the disease-specific mutations are thought to affect different DNA repair pathways, the molecular basis for this is unknown. Here we examine the function of XPF-ERCC1 in DNA interstrand crosslink (ICL) repair. We used Xenopus egg extracts to measure both ICL and nucleotide excision repair, and we identified mutations that are specifically defective in ICL repair. One of these separation-of-function mutations resides in the helicase-like domain of XPF and disrupts binding to SLX4 and recruitment to the ICL A small deletion in the same domain supports recruitment of XPF to the ICL, but inhibited the unhooking incisions most likely by disrupting a second, transient interaction with SLX4. Finally, mutation of residues in the nuclease domain did not affect localization of XPF-ERCC1 to the ICL but did prevent incisions on the ICL substrate. Our data support a model in which the ICL repair-specific function of XPF-ERCC1 is dependent on recruitment, positioning and substrate recognition. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

ICL: The Image Composition Language

NASA Technical Reports Server (NTRS)

Foley, James D.; Kim, Won Chul

1986-01-01

The Image Composition Language (ICL) provides a convenient way for programmers of interactive graphics application programs to define how the video look-up table of a raster display system is to be loaded. The ICL allows one or several images stored in the frame buffer to be combined in a variety of ways. The ICL treats these images as variables, and provides arithematic, relational, and conditional operators to combine the images, scalar variables, and constants in image composition expressions. The objective of ICL is to provide programmers with a simple way to compose images, to relieve the tedium usually associated with loading the video look-up table to obtain desired results.

Inhibition of the Nedd8 system sensitizes cells to DNA Inter-strand crosslinking agents

PubMed Central

Kee, Younghoon; Huang, Min; Chang, Sophia; Moreau, Lisa A.; Park, Eunmi; Smith, Peter G.; D’Andrea, Alan D.

2012-01-01

The Fanconi Anemia (FA) pathway is required for repair of DNA interstrand crosslinks (ICLs). FA pathway-deficient cells are hypersensitive to DNA ICL-inducing drugs such as Cisplatin. Conversely, hyperactivation of the FA pathway is a mechanism that may underlie cellular resistance to DNA ICL agents. Modulating FANCD2 monoubiquitination, a key step in the FA pathway, may be an effective therapeutic approach to conferring cellular sensitivity to ICL agents. Here, we show that inhibition of the Nedd8 conjugation system increases cellular sensitivity to DNA ICL-inducing agents. Mechanistically, the Nedd8 inhibition, either by siRNA-mediated knockdown of Nedd8 conjugating enzymes or treatment with a Nedd8 activating enzyme inhibitor MLN4924, suppressed DNA damage-induced FANCD2 monoubiquitination and CHK1 phosphorylation. Our data indicate that inhibition of the FA pathway is largely responsible for the heightened cellular sensitivity to DNA ICLs upon Nedd8 inhibition. These results suggest that a combination of Nedd8 inhibition with ICL-inducing agents may be an effective strategy for sensitizing a subset of drug-resistant cancer cells. PMID:22219386

DNA interstrand cross-link repair: understanding role of Fanconi anemia pathway and therapeutic implications.

PubMed

Shukla, Pallavi; Solanki, Avani; Ghosh, Kanjaksha; Vundinti, Babu Rao

2013-11-01

Interstrand cross-links (ICLs) are extremely toxic DNA lesions that prevent DNA double-helix separation due to the irreversible covalent linkage binding of some agents on DNA strands. Agents that induce these ICLs are thus widely used as chemotherapeutic drugs but may also lead to tumor growth. Fanconi anemia (FA) is a rare genetic disorder that leads to ICL sensitivity. This review provides update on current understanding of the role of FA proteins in repairing ICLs at various stages of cell cycle. We also discuss link between DNA cross-link genotoxicity caused by aldehydes in FA pathway. Besides this, we summarize various ICL agents that act as drugs to treat different types of tumors and highlight strategies for modulating ICL sensitivity for therapeutic interventions that may be helpful in controlling cancer and life-threatening disease, FA. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Long-Term Comparison of Posterior Chamber Phakic Intraocular Lens With and Without a Central Hole (Hole ICL and Conventional ICL) Implantation for Moderate to High Myopia and Myopic Astigmatism: Consort-Compliant Article.

PubMed

Shimizu, Kimiya; Kamiya, Kazutaka; Igarashi, Akihito; Kobashi, Hidenaga

2016-04-01

The study shows a promising next-generation surgical option for the correction of moderate to high ametropia. Hole implantable collamer lens (ICL), STAAR Surgical, is a posterior chamber phakic intraocular lens with a central artificial hole. As yet, however, no long-term comparison of the clinical results of the implantation of ICLs with and without such a hole has hitherto been conducted. A prospective, randomized, controlled trial was carried out in order to compare the long-term clinical outcomes of the implantation, in such eyes, of ICLs with and without a central artificial hole.Examinations were conducted of the 64 eyes of 32 consecutive patients with spherical equivalents of -7.53 ± 2.39 diopters (D) (mean ± standard deviation) in whom implantation of a Hole ICL was performed in 1 eye, and that of a conventional ICL was carried out in the other, by randomized assignment. Before 1, 3, and 6 months, and 1, 3, and 5 years after surgery, the safety, efficacy, predictability, stability, intraocular pressure, endothelial cell density, and adverse events of the 2 surgical techniques were assessed and compared over time.The measurements of LogMAR uncorrected and corrected distance visual acuity 5 years postoperatively were -0.17 ± 0.14 and -0.24 ± 0.08 in the Hole ICL group, and -0.16 ± 0.10 and -0.25 ± 0.08 in the conventional ICL group. In these 2 groups, 96% and 100% of eyes, respectively, were within 1.0 D of the targeted correction 5 years postoperatively. Manifest refraction changed by -0.17 ± 0.41 D and -0.10 ± 0.26 D occurred in from 1 month to 5 years in the Hole and conventional ICL groups, respectively. Only 1 eye (3.1%), which was in the conventional ICL group, developed an asymptomatic anterior subcapsular cataract.Both Hole and conventional ICLs corrected of ametropia successfully throughout the 5-year observation period. It appears likely that the presence of the central hole does not significantly affect these visual and refractive outcomes. UMIN000018771.

A prospective comparison of phakic collamer lenses and wavefront-optimized laser-assisted in situ keratomileusis for correction of myopia

PubMed Central

Parkhurst, Gregory D

2016-01-01

Purpose The aim of this study was to evaluate and compare night vision and low-luminance contrast sensitivity (CS) in patients undergoing implantation of phakic collamer lenses or wavefront-optimized laser-assisted in situ keratomileusis (LASIK). Patients and methods This is a nonrandomized, prospective study, in which 48 military personnel were recruited. Rabin Super Vision Test was used to compare the visual acuity and CS of Visian implantable collamer lens (ICL) and LASIK groups under normal and low light conditions, using a filter for simulated vision through night vision goggles. Results Preoperative mean spherical equivalent was −6.10 D in the ICL group and −6.04 D in the LASIK group (P=0.863). Three months postoperatively, super vision acuity (SVa), super vision acuity with (low-luminance) goggles (SVaG), super vision contrast (SVc), and super vision contrast with (low luminance) goggles (SVcG) significantly improved in the ICL and LASIK groups (P<0.001). Mean improvement in SVaG at 3 months postoperatively was statistically significantly greater in the ICL group than in the LASIK group (mean change [logarithm of the minimum angle of resolution, LogMAR]: ICL =−0.134, LASIK =−0.085; P=0.032). Mean improvements in SVc and SVcG were also statistically significantly greater in the ICL group than in the LASIK group (SVc mean change [logarithm of the CS, LogCS]: ICL =0.356, LASIK =0.209; P=0.018 and SVcG mean change [LogCS]: ICL =0.390, LASIK =0.259; P=0.024). Mean improvement in SVa at 3 months was comparable in both groups (P=0.154). Conclusion Simulated night vision improved with both ICL implantation and wavefront-optimized LASIK, but improvements were significantly greater with ICLs. These differences may be important in a military setting and may also affect satisfaction with civilian vision correction. PMID:27418804

A prospective comparison of phakic collamer lenses and wavefront-optimized laser-assisted in situ keratomileusis for correction of myopia.

PubMed

Parkhurst, Gregory D

2016-01-01

The aim of this study was to evaluate and compare night vision and low-luminance contrast sensitivity (CS) in patients undergoing implantation of phakic collamer lenses or wavefront-optimized laser-assisted in situ keratomileusis (LASIK). This is a nonrandomized, prospective study, in which 48 military personnel were recruited. Rabin Super Vision Test was used to compare the visual acuity and CS of Visian implantable collamer lens (ICL) and LASIK groups under normal and low light conditions, using a filter for simulated vision through night vision goggles. Preoperative mean spherical equivalent was -6.10 D in the ICL group and -6.04 D in the LASIK group (P=0.863). Three months postoperatively, super vision acuity (SVa), super vision acuity with (low-luminance) goggles (SVaG), super vision contrast (SVc), and super vision contrast with (low luminance) goggles (SVcG) significantly improved in the ICL and LASIK groups (P<0.001). Mean improvement in SVaG at 3 months postoperatively was statistically significantly greater in the ICL group than in the LASIK group (mean change [logarithm of the minimum angle of resolution, LogMAR]: ICL =-0.134, LASIK =-0.085; P=0.032). Mean improvements in SVc and SVcG were also statistically significantly greater in the ICL group than in the LASIK group (SVc mean change [logarithm of the CS, LogCS]: ICL =0.356, LASIK =0.209; P=0.018 and SVcG mean change [LogCS]: ICL =0.390, LASIK =0.259; P=0.024). Mean improvement in SVa at 3 months was comparable in both groups (P=0.154). Simulated night vision improved with both ICL implantation and wavefront-optimized LASIK, but improvements were significantly greater with ICLs. These differences may be important in a military setting and may also affect satisfaction with civilian vision correction.

Characterizing Intracluster Light in the Hubble Frontier Fields

NASA Astrophysics Data System (ADS)

Morishita, Takahiro; Abramson, Louis E.; Treu, Tommaso; Schmidt, Kasper B.; Vulcani, Benedetta; Wang, Xin

2017-09-01

We investigate the intracluster light (ICL) in the six Hubble Frontier Field clusters at 0.3< z< 0.6. We employ a new method, which is free from any functional form of the ICL profile, and exploit the unprecedented depth of this Hubble Space Telescope imaging to map the ICL’s diffuse light out to clustrocentric radii R˜ 300 {kpc} ({μ }{ICL}˜ 27 mag arcsec-2). From these maps, we construct radial color and stellar mass profiles via SED fitting and find clear negative color gradients in all systems with increasing distance from the Brightest Cluster Galaxy (BCG). While this implies older/more metal-rich stellar components in the inner part of the ICL, we find that the ICL mostly consists of a ≲ 2 {Gyr} population, and plausibly originated with {log}{M}* /{M}⊙ ≲ 10 cluster galaxies. Furthermore, we find that 10%-15% of the ICL’s mass at large radii (≳ 150 kpc) lies in a younger/bluer stellar population (˜1 Gyr), a phenomenon not seen in local samples. We attribute this light to the higher fraction of star-forming/(post-)starburst galaxies in clusters at z˜ 0.5. Ultimately, we find the ICL’s total mass to be {log}{M}* {ICL}/{M}⊙ ˜ 11-12, constituting 5%-20% of the clusters’ total stellar mass, or about half of the value at z˜ 0. The above implies distinct formation histories for the ICL and BCGs/other massive cluster galaxies; I.e., the ICL at this epoch is still being constructed rapidly (˜ 40 {M}⊙ yr-1), while the BCGs have mostly completed their evolution. To be consistent with the ICL measurements of local massive clusters, such as Virgo, our data suggest mass acquisition mainly from quiescent cluster galaxies is the principal source of ICL material in the subsequent ˜5 Gyr of cosmic time.

Protein kinase C enhances the swelling-induced chloride current in human atrial myocytes.

PubMed

Li, Ye-Tao; Du, Xin-Ling

2016-06-01

Swelling-activated chloride currents (ICl.swell) are thought to play a role in several physiologic and pathophysiologic processes and thus represent a target for therapeutic approaches. However, the mechanism of ICl.swell regulation remains unclear. In this study, we used the whole-cell patch-clamp technique to examine the role of protein kinase C (PKC) in the regulation of ICl.swell in human atrial myocytes. Atrial myocytes were isolated from the right atrial appendages of patients undergoing coronary artery bypass and enzymatically dissociated. ICl.swell was evoked in hypotonic solution and recorded using the whole-cell patch-clamp technique. The PKC agonist phorbol dibutyrate (PDBu) enhanced ICl.swell in a concentration-dependent manner, which was reversed in isotonic solution and by a chloride current inhibitor, 9-anthracenecarboxylicacid. Furthermore, the PKC inhibitor bis-indolylmaleimide attenuated the effect and 4α-PDBu, an inactive PDBu analog, had no effect on ICl.swell. These results, obtained using the whole-cell patch-clamp technique, demonstrate the ability of PKC to activate ICl,swell in human atrial myocytes. This observation was consistent with a previous study using a single-channel patch-clamp technique, but differed from some findings in other species.

The Fanconi Anemia Pathway in Replication Stress and DNA Crosslink Repair

PubMed Central

Jones, Mathew JK.; Huang, Tony T.

2013-01-01

Interstand crosslinks (ICLs) are DNA lesions where the bases of opposing DNA strands are covalently linked, inhibiting critical cellular processes such as transcription and replication. Chemical agents that generate ICLs cause chromosomal abnormalities including breaks, deletions and rearrangements, making them highly genotoxic compounds. This toxicity has proven useful for chemotherapeutic treatment against a wide variety of cancer types. The majority of our understanding of ICL repair in humans has been uncovered thorough analysis of the rare genetic disorder Fanconi anemia, in which patients are extremely sensitive to crosslinking agents. Here, we discuss recent insights into ICL repair gained through new ICL repair assays and highlight the role of the Fanconi Anemia repair pathway during replication stress. PMID:22744751

Intergalactic stellar populations in intermediate redshift clusters

NASA Astrophysics Data System (ADS)

Melnick, J.; Giraud, E.; Toledo, I.; Selman, F.; Quintana, H.

2012-11-01

A substantial fraction of the total stellar mass in rich clusters of galaxies resides in a diffuse intergalactic component usually referred to as the intracluster light (ICL). Theoretical models indicate that these intergalactic stars originate mostly from the tidal interaction of the cluster galaxies during the assembly history of the cluster, and that a significant fraction of these stars could have formed in situ from the late infall of cold metal-poor gas clouds on to the cluster. However, these models also overpredict the fraction of stellar mass in the ICL by a substantial margin, something that is still not well understood. The models also make predictions about the age distribution of the ICL stars, which may provide additional observational constraints. Here we present population synthesis models for the ICL of an intermediate redshift (z = 0.29) X-ray cluster that we have extensively studied in previous papers. The advantage of observing intermediate redshift clusters rather than nearby ones is that the former fit the field of view of multi-object spectrographs in 8-m telescopes and therefore permit us to encompass most of the ICL with only a few well-placed slits. In this paper we show that by stacking spectra at different locations within the ICL it is possible to reach sufficiently high signal-to-noise ratios to fit population synthesis models and derive meaningful results. The models provide ages and metallicities for the dominant populations at several different locations within the ICL and the brightest cluster galaxies (BCG) halo, as well as measures of the kinematics of the stars as a function of distance from the BCG. We thus find that the ICL in our cluster is dominated by old metal-rich stars, at odds with what has been found in nearby clusters where the stars that dominate the ICL are old and metal poor. While we see weak evidence of a young, metal-poor component, if real, these young stars would amount to less than 1 per cent of the total ICL mass, much less than the up to 30 per cent predicted by the models. We propose that the very metal-rich (i.e. 2.5× solar) stars in the ICL of our cluster, which comprise ˜40 per cent of the total mass, originate mostly from the central dumb-bell galaxy, while the remaining solar and metal-poor stars come from spiral, post-starburst (E+A) and metal-poor dwarf galaxies. About 16 per cent of the ICL stars are old and metal poor.

Single-Mode, Distributed Feedback Interband Cascade Lasers

NASA Technical Reports Server (NTRS)

Frez, Clifford F. (Inventor); Borgentun, Carl E. (Inventor); Briggs, Ryan M. (Inventor); Bagheri, Mahmood (Inventor); Forouhar, Siamak (Inventor)

2016-01-01

Single-mode, distributed feedback interband cascade lasers (ICLs) using distributed-feedback gratings (e.g., lateral Bragg gratings) and methods of fabricating such ICLs are provided. The ICLs incorporate distributed-feedback gratings that are formed above the laser active region and adjacent the ridge waveguide (RWG) of the ICL. The ICLs may incorporate a double-ridge system comprising an optical confinement structure (e.g., a RWG) disposed above the laser active region that comprises the first ridge of the double ridge system, a DFB grating (e.g., lateral Bragg grating) disposed above the laser active region and adjacent the optical confinement structure, and an electric confinement structure that passes at least partially through the laser active region and that defines the boundary of the second ridge comprises and the termination of the DFB grating.

Chromosomal Integrity after UV Irradiation Requires FANCD2-Mediated Repair of Double Strand Breaks

PubMed Central

Federico, María Belén; Vallerga, María Belén; Radl, Analía; Paviolo, Natalia Soledad; Bocco, José Luis; Di Giorgio, Marina; Soria, Gastón; Gottifredi, Vanesa

2016-01-01

Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor of the FA pathway, is essential for the repair of double strand breaks (DSBs) generated during fork collapse at ICLs. While lesions different from ICLs can also trigger fork collapse, the contribution of FANCD2 to the resolution of replication-coupled DSBs generated independently from ICLs is unknown. Intriguingly, FANCD2 is readily activated after UV irradiation, a DNA-damaging agent that generates predominantly intra-strand crosslinks but not ICLs. Hence, UV irradiation is an ideal tool to explore the contribution of FANCD2 to the DNA damage response triggered by DNA lesions other than ICL repair. Here we show that, in contrast to ICL-causing agents, UV radiation compromises cell survival independently from FANCD2. In agreement, FANCD2 depletion does not increase the amount of DSBs generated during the replication of UV-damaged DNA and is dispensable for UV-induced checkpoint activation. Remarkably however, FANCD2 protects UV-dependent, replication-coupled DSBs from aberrant processing by non-homologous end joining, preventing the accumulation of micronuclei and chromatid aberrations including non-homologous chromatid exchanges. Hence, while dispensable for cell survival, FANCD2 selectively safeguards chromosomal stability after UV-triggered replication stress. PMID:26765540

Chromosomal Integrity after UV Irradiation Requires FANCD2-Mediated Repair of Double Strand Breaks.

PubMed

Federico, María Belén; Vallerga, María Belén; Radl, Analía; Paviolo, Natalia Soledad; Bocco, José Luis; Di Giorgio, Marina; Soria, Gastón; Gottifredi, Vanesa

2016-01-01

Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor of the FA pathway, is essential for the repair of double strand breaks (DSBs) generated during fork collapse at ICLs. While lesions different from ICLs can also trigger fork collapse, the contribution of FANCD2 to the resolution of replication-coupled DSBs generated independently from ICLs is unknown. Intriguingly, FANCD2 is readily activated after UV irradiation, a DNA-damaging agent that generates predominantly intra-strand crosslinks but not ICLs. Hence, UV irradiation is an ideal tool to explore the contribution of FANCD2 to the DNA damage response triggered by DNA lesions other than ICL repair. Here we show that, in contrast to ICL-causing agents, UV radiation compromises cell survival independently from FANCD2. In agreement, FANCD2 depletion does not increase the amount of DSBs generated during the replication of UV-damaged DNA and is dispensable for UV-induced checkpoint activation. Remarkably however, FANCD2 protects UV-dependent, replication-coupled DSBs from aberrant processing by non-homologous end joining, preventing the accumulation of micronuclei and chromatid aberrations including non-homologous chromatid exchanges. Hence, while dispensable for cell survival, FANCD2 selectively safeguards chromosomal stability after UV-triggered replication stress.

Intracluster light in clusters of galaxies at redshifts 0.4 < z < 0.8

NASA Astrophysics Data System (ADS)

Guennou, L.; Adami, C.; Da Rocha, C.; Durret, F.; Ulmer, M. P.; Allam, S.; Basa, S.; Benoist, C.; Biviano, A.; Clowe, D.; Gavazzi, R.; Halliday, C.; Ilbert, O.; Johnston, D.; Just, D.; Kron, R.; Kubo, J. M.; Le Brun, V.; Marshall, P.; Mazure, A.; Murphy, K. J.; Pereira, D. N. E.; Rabaça, C. R.; Rostagni, F.; Rudnick, G.; Russeil, D.; Schrabback, T.; Slezak, E.; Tucker, D.; Zaritsky, D.

2012-01-01

Context. The study of intracluster light (ICL) can help us to understand the mechanisms taking place in galaxy clusters, and to place constraints on the cluster formation history and physical properties. However, owing to the intrinsic faintness of ICL emission, most searches and detailed studies of ICL have been limited to redshifts z < 0.4. Aims: To help us extend our knowledge of ICL properties to higher redshifts and study the evolution of ICL with redshift, we search for ICL in a subsample of ten clusters detected by the ESO Distant Cluster Survey (EDisCS), at redshifts 0.4 < z < 0.8, that are also part of our DAFT/FADA Survey. Methods: We analyze the ICL by applying the OV WAV package, a wavelet-based technique, to deep HST ACS images in the F814W filter and to V-band VLT/FORS2 images of three clusters. Detection levels are assessed as a function of the diffuse light source surface brightness using simulations. Results: In the F814W filter images, we detect diffuse light sources in all the clusters, with typical sizes of a few tens of kpc (assuming that they are at the cluster redshifts). The ICL detected by stacking the ten F814W images shows an 8σ detection in the source center extending over a ~50 × 50 kpc2 area, with a total absolute magnitude of -21.6 in the F814W filter, equivalent to about two L∗ galaxies per cluster. We find a weak correlation between the total F814W absolute magnitude of the ICL and the cluster velocity dispersion and mass. There is no apparent correlation between the cluster mass-to-light ratio (M/L) and the amount of ICL, and no evidence of any preferential orientation in the ICL source distribution. We find no strong variation in the amount of ICL between z = 0 and z = 0.8. In addition, we find wavelet-detected compact objects (WDCOs) in the three clusters for which data in two bands are available; these objects are probably very faint compact galaxies that in some cases are members of the respective clusters and comparable to the faint dwarf galaxies of the Local Group. Conclusions: We show that the ICL is prevalent in clusters at least up to redshift z = 0.8. In the future, we propose to detect the ICL at even higher redshifts, to determine wether there is a particular stage of cluster evolution where it was stripped from galaxies and spread into the intracluster medium. Based on observations made at ESO Telescopes at the Paranal Observatory under programme ID 082.A-0374. Also based on the use of the NASA/IPAC Extragalactic Database (NED) which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration. Based on observations made with the NASA/ESA Hubble Space Telescope, obtained from the data archives at the Space Telescope European Coordinating Facility and the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555.

RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health.

PubMed

Feeney, Laura; Muñoz, Ivan M; Lachaud, Christophe; Toth, Rachel; Appleton, Paul L; Schindler, Detlev; Rouse, John

2017-06-01

Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in ICL repair. An amino acid substitution in the WD40 repeats of RFWD3 (I639K) found in a new FA subtype abolishes interaction of RFWD3 with RPA, thereby preventing RFWD3 recruitment to sites of ICL-induced replication fork stalling. Moreover, single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit ICL repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. We also report that unloading of RPA from sites of ICL induction is perturbed in RFWD3-deficient cells. These data reveal important roles for RFWD3 localization in protecting genome stability and preserving human health. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

RPA activates the XPF-ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks.

PubMed

Abdullah, Ummi B; McGouran, Joanna F; Brolih, Sanja; Ptchelkine, Denis; El-Sagheer, Afaf H; Brown, Tom; McHugh, Peter J

2017-07-14

During replication-coupled DNA interstrand crosslink (ICL) repair, the XPF-ERCC1 endonuclease is required for the incisions that release, or "unhook", ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL Here, we report that while purified XPF-ERCC1 incises simple ICL-containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity. Strikingly, the addition of the single-stranded DNA (ssDNA)-binding replication protein A (RPA) selectively restores XPF-ERCC1 endonuclease activity on this structure. The 5'-3' exonuclease SNM1A can load from the XPF-ERCC1-RPA-induced incisions and digest past the crosslink to quantitatively complete the unhooking reaction. We postulate that these collaborative activities of XPF-ERCC1, RPA and SNM1A might explain how ICL unhooking is achieved in vivo . © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Interface Circuits for Self-Checking Microprocessors

NASA Technical Reports Server (NTRS)

Rennels, D. A.; Chandramouli, R.

1986-01-01

Fault-tolerant-microcomputer concept based on enhancing "simple" computer with redundancy and self-checking logic circuits detect hardware faults. Interface and checking logic and redundant processors confer on 16-bit microcomputer ability to check itself for hardware faults. Checking circuitry also checks itself. Concept of self-checking complementary pairs (SCCP's) employed throughout ICL unit.

The Fanconi anemia pathway promotes replication-dependent DNA interstrand crosslink repair

PubMed Central

Knipscheer, Puck; Räschle, Markus; Smogorzewska, Agata; Enoiu, Milica; Ho, The Vinh; Schärer, Orlando D.; Elledge, Stephen J.; Walter, Johannes C.

2010-01-01

Fanconi anemia is a human cancer predisposition syndrome caused by mutations in thirteen Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand crosslinks (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. We make use of a cell-free system to show that the FANCI-FANCD2 complex is required for replication-dependent ICL repair. Removal of FANCD2 from extracts inhibits nucleolytic incisions near the ICL as well as translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised. PMID:19965384

The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair.

PubMed

Knipscheer, Puck; Räschle, Markus; Smogorzewska, Agata; Enoiu, Milica; Ho, The Vinh; Schärer, Orlando D; Elledge, Stephen J; Walter, Johannes C

2009-12-18

Fanconi anemia is a human cancer predisposition syndrome caused by mutations in 13 Fanc genes. The disorder is characterized by genomic instability and cellular hypersensitivity to chemicals that generate DNA interstrand cross-links (ICLs). A central event in the activation of the Fanconi anemia pathway is the mono-ubiquitylation of the FANCI-FANCD2 complex, but how this complex confers ICL resistance remains enigmatic. Using a cell-free system, we showed that FANCI-FANCD2 is required for replication-coupled ICL repair in S phase. Removal of FANCD2 from extracts inhibits both nucleolytic incisions near the ICL and translesion DNA synthesis past the lesion. Reversal of these defects requires ubiquitylated FANCI-FANCD2. Our results show that multiple steps of the essential S-phase ICL repair mechanism fail when the Fanconi anemia pathway is compromised.

Flexible metabolism in Metarhizium anisopliae and Beauveria bassiana: role of the glyoxylate cycle during insect pathogenesis.

PubMed

Padilla-Guerrero, Israel Enrique; Barelli, Larissa; González-Hernández, Gloria Angélica; Torres-Guzmán, Juan Carlos; Bidochka, Michael J

2011-01-01

Insect pathogenic fungi such as Metarhizium anisopliae and Beauveria bassiana have an increasing role in the control of agricultural insect pests and vectors of human diseases. Many of the virulence factors are well studied but less is known of the metabolism of these fungi during the course of insect infection or saprobic growth. Here, we assessed enzyme activity and gene expression in the central carbon metabolic pathway, including isocitrate dehydrogenase, aconitase, citrate synthase, malate synthase (MLS) and isocitrate lyase (ICL), with particular attention to the glyoxylate cycle when M. anisopliae and B. bassiana were grown under various conditions. We observed that ICL and MLS, glyoxylate cycle intermediates, were upregulated during growth on 2-carbon compounds (acetate and ethanol) as well as in insect haemolymph. We fused the promoter of the M. anisopliae ICL gene (Ma-icl) to a marker gene (mCherry) and showed that Ma-icl was upregulated when M. anisopliae was grown in the presence of acetate. Furthermore, Ma-icl was upregulated when fungi were engulfed by insect haemocytes as well as during appressorium formation. Addition of the ICL inhibitor 3-nitroproprionate delayed conidial germination and inhibited appressorium formation. These results show that these insect pathogenic fungi have a flexible metabolism that includes the glyoxylate cycle as an integral part of germination, pathogenesis and saprobic growth.

Gamma irradiation of Fabry–Perot interband cascade lasers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Myers, Tanya L.; Cannon, Bret D.; Brauer, Carolyn S.

Two Fabry-Perot interband cascade lasers (ICLs) were exposed to Cobalt-60 gamma rays for a dosage of 500 krad(Si) each, which is higher than is typically encountered in space applications. The ICLs do not show any significant changes in threshold current or slope efficiency, suggesting the suitability of ICLs for use in radiation environments.

Identification of a novel inhibitor of isocitrate lyase as a potent antitubercular agent against both active and non-replicating Mycobacterium tuberculosis.

PubMed

Liu, Yishuang; Zhou, Shuang; Deng, Qi; Li, Xinghua; Meng, Jianzhou; Guan, Yan; Li, Chuanyou; Xiao, Chunling

2016-03-01

Screen and identify novel inhibitors of isocitrate lyase (ICL) as potent antitubercular agents against Mycobacterium tuberculosis and determine their inhibitory characteristics, antitubercular activities and mechanisms of action. Recombinant ICL of M. tuberculosis was expressed and purified, which was used for high-throughput screening (HTS) and the following experiments. A total of 71,765 compounds were screened to identify ICL inhibitors which were then evaluated for their roles as potent antitubercular agents. To determine the inhibitory characteristics of the agents against latent M. tuberculosis in persistent infections, a macrophage model (mouse J774A.1 cell) infected with Mycobacterium marinum BAA-535 strain was built and assessed. The potent antitubercular agents were identified using the macrophage model. Then, the inhibitory intensity and mode of the agents that exhibit on ICL protein of M. tuberculosis were analyzed, and the interaction mechanisms were preliminarily clarified according to the parameters of enzyme kinetics, circular dichroism experiments, fluorescence quenching assay, and molecular docking. The previously established ICL inhibitor screening model was evaluated to be suitable for HTS assay. Of the 71,765 compounds, 13 of them were identified to inhibit ICL effectively and stably. IMBI-3 demonstrated the most significant inhibitory activity with IC50 of 30.9 μmol/L. Its minimum inhibitory concentration (MIC) for M. tuberculosis, including extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant tuberculosis (MDR-TB), were determined in the range of 0.25-1 μg/mL. When IMBI-3 is used in combination with isoniazid, the colony-forming units (CFU) counting of latent M. tuberculosis in J774A.1 macrophage cells decreased significantly as IMBI-3 concentration increased. The inhibition mode of IMBI-3 on ICL was probably competitive inhibition with an inhibition constant (Ki) of approximate 1.85 μmol/L. The interaction between IMBI-3 and ICL of M. tuberculosis was also confirmed by circular dichroism experiments and fluorescence quenching assay. And seven possible active amino acids of ICL of M. tuberculosis were identified in the active site through molecular docking. IMBI-3, a novel potent antitubercular agent targeting ICL of M. tuberculosis, was identified and evaluated. It inhibited both log-phase M. tuberculosis in vitro and dormant M. tuberculosis in macrophages. It was the first representative compound of this family with the ICL enzyme inhibition and antimycobacterial activities. Copyright © 2016 Elsevier Ltd. All rights reserved.

The different growth pathways of Brightest Cluster Galaxies and the Intra-Cluster Light

NASA Astrophysics Data System (ADS)

Contini, E.; Yi, S. K.; Kang, X.

2018-06-01

We study the growth pathways of Brightest Central Galaxies (BCGs) and Intra-Cluster Light (ICL) by means of a semi-analytic model. We assume that the ICL forms by stellar stripping of satellite galaxies and violent processes during mergers, and implement two independent models: (1) one considers both mergers and stellar stripping (named STANDARD model), and one considers only mergers (named MERGERS model). We find that BCGs and ICL form, grow and overall evolve at different times and with different timescales, but they show a clear co-evolution after redshift z ˜ 0.7 - 0.8. Around 90% of the ICL from stellar stripping is built-up in the innermost 150 Kpc from the halo centre and the dominant contribution comes from disk-like galaxies (B/T<0.4) through a large number of small/intermediate stripping events (Mstrip/Msat < 0.3). The fractions of stellar mass in BCGs and in ICL over the total stellar mass within the virial radius of the halo evolve differently with time. At high redshift, the BCG accounts for the bulk of the mass, but its contribution gradually decreases with time and stays constant after z ˜ 0.4 - 0.5. The ICL, instead, grows very fast and its contribution keeps increasing down to the present time. The STANDARD and the MERGERS models make very similar predictions in most of the cases, but predict different amounts of ICL associated to other galaxies within the virial radius of the group/cluster other than the BCG, at z = 0. We then suggest that this quantity is a valid observable that can shed light on the relative importance of mergers and stellar stripping for the formation of the ICL.

Requirement of the isocitrate lyase gene ICL1 for VPS41-mediated starvation response in Cryptococcus neoformans.

PubMed

Xu, Zhe; Zhi, Yafei; Dong, Jianzhang; Lin, Benfeng; Ye, Di; Liu, Xiaoguang

2016-07-01

Cryptococcus neoformans is a major cause of fungal meningitis in individuals with impaired immunity. Our previous studies have shown that the VPS41 gene plays a critical role in the survival of Cryptococcus neoformans under nitrogen starvation; however, the molecular mechanisms underlying VPS41-mediated starvation response remain to be elucidated. In the present study, we show that, under nitrogen starvation, VPS41 strongly enhanced ICL1 expression in C. neoformans and that overexpression of ICL1 in the vps41 mutant dramatically suppressed its defects in starvation response due to the loss of VPS41 function. Moreover, targeted deletion of ICL1 resulted in a dramatic decline in viability of C. neoformans cells under nitrogen deprivation. Taken together, our data suggest a model in which VPS41 up-regulates ICL1 expression, directly or indirectly, to promote survival of C. neoformans under nitrogen starvation.

NMR structural study of the intracellular loop 3 of the serotonin 5-HT(1A) receptor and its interaction with calmodulin.

PubMed

Chen, Angela Shuyi; Kim, Young Mee; Gayen, Shovanlal; Huang, Qiwei; Raida, Manfred; Kang, Congbao

2011-09-01

The serotonin (5-HT(1A)) receptor, a G-protein-coupled receptor (GPCR), plays important roles in serotonergic signaling in the central nervous system. The third intracellular loop (ICL3) of the 5-HT(1A) receptor has been shown to be important for the regulation of this receptor through interactions with proteins such as G-proteins and calmodulin. In this study, the ICL3 of 5-HT(1A) receptor was expressed in E. coli and purified. Gel filtration and mass spectrometry were used to confirm the molecular weight of the purified ICL3. Secondary structure analysis using circular dichroism (CD) demonstrated the presence of α-helical structures. Backbone assignment of ICL3 was achieved using three-dimensional experiments. A chemical shift index and Talos+ analysis showed that residues E326 to R339 form α-helical structure. Residues G256 to S269 of ICL3 were shown to be a novel region that has a molecular interaction with calmodulin in titration assays. Peptide derived from the ICL3 containing residues from G256 to S269 also showed molecular interaction with calmodulin. Copyright © 2011 Elsevier B.V. All rights reserved.

In vivo confocal Raman microscopic determination of depth profiles of the stratum corneum lipid organization influenced by application of various oils.

PubMed

Choe, ChunSik; Schleusener, Johannes; Lademann, Jürgen; Darvin, Maxim E

2017-08-01

The intercellular lipids (ICL) of stratum corneum (SC) play an important role in maintaining the skin barrier function. The lateral and lamellar packing order of ICL in SC is not homogenous, but rather depth-dependent. This study aimed to analyze the influence of the topically applied mineral-derived (paraffin and petrolatum) and plant-derived (almond oil and jojoba oil) oils on the depth-dependent ICL profile ordering of the SC in vivo. Confocal Raman microscopy (CRM), a unique tool to analyze the depth profile of the ICL structure non-invasively, is employed to investigate the interaction between oils and human SC in vivo. The results show that the response of SC to oils' permeation varies in the depths. All oils remain in the upper layers of the SC (0-20% of SC thickness) and show predominated differences of ICL ordering from intact skin. In these depths, skin treated with plant-derived oils shows more disordered lateral and lamellar packing order of ICL than intact skin (p<0.05). In the intermediate layers of SC (30-50% of SC thickness), the oils do not influence the lateral packing order of SC ICL (p>0.1), except plant-derived oils at the depth 30% of SC thickness. In the deeper layers of the SC (60-100% of SC thickness), no difference between ICL lateral packing order of the oil-treated and intact skin can be observed, except that at the depths of 70-90% of the SC thickness, where slight changes with more disorder states are measured for plant-derived oil treated skin (p<0.1), which could be explained by the penetration of free fatty acid fractions in the deep-located SC areas. Both oil types remain in the superficial layers of the SC (0-20% of the SC thickness). Skin treated with mineral- and plant-derived oils shows significantly higher disordered lateral and lamellar packing order of ICL in these layers of the SC compared to intact skin. Plant-derived oils significantly changed the ICL ordering in the depths of 30% and 70-90% of the SC thickness, which is likely due to the penetration of free fatty acids in the deeper layers of the SC. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

DIFFERENTIAL ROLE OF BASE EXCISION REPAIR PROTEINS IN MEDIATING CISPLATIN CYTOTOXICITY

PubMed Central

Sawant, Akshada; Floyd, Ashley M.; Dangeti, Mohan; Lei, Wen; Sobol, Robert W.; Patrick, Steve M.

2017-01-01

Interstrand crosslinks (ICLs) are covalent lesions formed by cisplatin. The mechanism for the processing and removal of ICLs by DNA repair proteins involves nucleotide excision repair (NER), homologous recombination (HR) and fanconi anemia (FA) pathways. In this report, we monitored the processing of a flanking uracil adjacent to a cisplatin ICL by the proteins involved in the base excision repair (BER) pathway. Using a combination of extracts, purified proteins, inhibitors, functional assays and cell culture studies, we determined the specific BER proteins required for processing a DNA substrate with a uracil adjacent to a cisplatin ICL. Uracil DNA glycosylase (UNG) is the primary glycosylase responsible for the removal of uracils adjacent to cisplatin ICLs, whereas other uracil glycosylases can process uracils in the context of undamaged DNA. Repair of the uracil adjacent to cisplatin ICLs proceeds through the classical BER pathway, highlighting the importance of specific proteins in this redundant pathway. Removal of uracil is followed by the generation of an abasic site and subsequent cleavage by AP endonuclease 1 (APE1). Inhibition of either the repair or redox domain of APE1 gives rise to cisplatin resistance. Inhibition of the lyase domain of Polymerase β (Polβ) does not influence cisplatin cytotoxicity. In addition, lack of XRCC1 leads to increased DNA damage and results in increased cisplatin cytotoxicity. Our results indicate that BER activation at cisplatin ICLs influences crosslink repair and modulates cisplatin cytotoxicity via specific UNG, APE1 and Polβ polymerase functions. PMID:28110804

Effects of Ti-Based Additives on the Hydrogen Storage Properties of a L i B H 4 / C a H 2 Destabilized System

DOE PAGES

Yang, Hongwei; Ibikunle, Adeola; Goudy, Andrew J.

2010-01-01

Tmore » he hydrogen storage properties of a destabilized LiBH 4 / CaH 2 system ball-milled with iCl 3 , iF 3 , and iO 2 additives have been investigated. It is found that the system with iCl 3 additive has a lower dehydrogenation temperature than the ones with other additives. Further study shows that a higher amount of iCl 3 is more effective in reducing the desorption temperature of the LiBH 4 / CaH 2 system, since it leads to a lower activation energy of dehydrogenation. he activations energies for mixtures containing 4, 10, and 25 mol% of iCl 3 are 141, 126, and 110 kJ/mol, respectively. However, the benefits of higher amounts of iCl 3 are offset by a larger reduction in hydrogen capacity of the mixtures.« less

Inhibitors of the Glyoxylate Cycle Enzyme ICL1 in Candida albicans for Potential Use as Antifungal Agents

PubMed Central

Cheah, Hong-Leong; Lim, Vuanghao; Sandai, Doblin

2014-01-01

Candida albicans is an opportunistic pathogen that causes candidiasis in humans. In recent years, metabolic pathways in C. albicans have been explored as potential antifungal targets to treat candidiasis. The glyoxylate cycle, which enables C. albicans to survive in nutrient-limited host niches and its. Key enzymes (e.g., isocitrate lyase (ICL1), are particularly attractive antifungal targets for C. albicans. In this study, we used a new screening approach that better reflects the physiological environment that C. albicans cells experience during infection to identify potential inhibitors of ICL. Three compounds (caffeic acid (CAFF), rosmarinic acid (ROS), and apigenin (API)) were found to have antifungal activity against C. albicans when tested under glucose-depleted conditions. We further confirmed the inhibitory potential of these compounds against ICL using the ICL enzyme assay. Lastly, we assessed the bioavailability and toxicity of these compounds using Lipinski's rule-of-five and ADMET analysis. PMID:24781056

Differential role of base excision repair proteins in mediating cisplatin cytotoxicity.

PubMed

Sawant, Akshada; Floyd, Ashley M; Dangeti, Mohan; Lei, Wen; Sobol, Robert W; Patrick, Steve M

2017-03-01

Interstrand crosslinks (ICLs) are covalent lesions formed by cisplatin. The mechanism for the processing and removal of ICLs by DNA repair proteins involves nucleotide excision repair (NER), homologous recombination (HR) and fanconi anemia (FA) pathways. In this report, we monitored the processing of a flanking uracil adjacent to a cisplatin ICL by the proteins involved in the base excision repair (BER) pathway. Using a combination of extracts, purified proteins, inhibitors, functional assays and cell culture studies, we determined the specific BER proteins required for processing a DNA substrate with a uracil adjacent to a cisplatin ICL. Uracil DNA glycosylase (UNG) is the primary glycosylase responsible for the removal of uracils adjacent to cisplatin ICLs, whereas other uracil glycosylases can process uracils in the context of undamaged DNA. Repair of the uracil adjacent to cisplatin ICLs proceeds through the classical BER pathway, highlighting the importance of specific proteins in this redundant pathway. Removal of uracil is followed by the generation of an abasic site and subsequent cleavage by AP endonuclease 1 (APE1). Inhibition of either the repair or redox domain of APE1 gives rise to cisplatin resistance. Inhibition of the lyase domain of Polymerase β (Polβ) does not influence cisplatin cytotoxicity. In addition, lack of XRCC1 leads to increased DNA damage and results in increased cisplatin cytotoxicity. Our results indicate that BER activation at cisplatin ICLs influences crosslink repair and modulates cisplatin cytotoxicity via specific UNG, APE1 and Polβ polymerase functions. Copyright © 2017 Elsevier B.V. All rights reserved.

Matched population comparison of visual outcomes and patient satisfaction between 3 modalities for the correction of low to moderate myopic astigmatism

PubMed Central

Ganesh, Sri; Brar, Sheetal; Pawar, Archana

2017-01-01

Purpose To compare toric implantable collamer lens (T-ICL), femto-LASIK, and ReLEx SMILE for the treatment of low to moderate myopic astigmatism in terms of long-term visual and refractive outcomes and predictability of astigmatic correction. Materials and methods The study included 30 eyes from 30 patients between the age groups of 21 and 40 years, undergoing bilateral surgery with any of the three procedures – T-ICL, femto-LASIK, or ReLEx SMILE – for correction of myopic astigmatism within the range of −3 to −8 D spherical equivalent (SE), with a minimum astigmatism of −0.75 D. Patients were followed up at day 1, 1 month, 6 months, and 1 year. Results At 1 year, the mean cylinder reduced to −0.21±0.28, −0.17±0.36, and −0.22±0.28 D in the T-ICL, femto-LASIK, and ReLEx SMILE group, respectively. The predictability of astigmatism correction was comparable, with no statistically significant difference between the 3 groups (P>0.05). A total of 97% of eyes in ReLEx SMILE achieved a uncorrected distance visual acuity of 20/20 or better, compared to T-ICL (93%) and FS-LASIK (90%). However, gain in lines of corrected distant visual acuity (CDVA) was maximum in T-ICL group (60%). Four eyes in the femto-LASIK group had loss of CDVA by one line. Three eyes required exchange due to high vault and rotation of the T-ICL, which did not affect the final outcome. Conclusion All 3 modalities were effective for myopic astigmatism at the end of 1 year. Quality of vision and patient satisfaction with T-ICL and ReLEx SMILE were similar and better than FS-LASIK. However, slight chances of postoperative rotation and exchange exist with T-ICL, which warrant thorough preoperative planning. PMID:28740361

Improving the production of acetyl-CoA-derived chemicals in Escherichia coli BL21(DE3) through iclR and arcA deletion.

PubMed

Liu, Min; Ding, Yamei; Chen, Hailin; Zhao, Zhe; Liu, Huizhou; Xian, Mo; Zhao, Guang

2017-01-07

Acetyl-CoA-derived chemicals are suitable for multiple applications in many industries. The bio-production of these chemicals has become imperative owing to the economic and environmental problems. However, acetate overflow is the major drawback for acetyl-CoA-derived chemicals production. Approaches for overcoming acetate overflow may be beneficial for the production of acetyl-CoA-derived chemicals. In this study, a transcriptional regulator iclR was knocked out in E.coli BL21(DE3) to overcome acetate overflow and improve the chemicals production. Two important acetyl-CoA-derived chemicals, phloroglucinol (PG) and 3-hydroxypropionate (3HP) were used to evaluate it. It is revealed that knockout of iclR significantly increased expressions of aceBAK operon. The cell yields and glucose utilization efficiencies were higher than those of control strains. The acetate concentrations were decreased by more than 50% and the productions of PG and 3HP were increased more than twice in iclR mutants. The effects of iclR knockout on cell physiology, cell metabolism and production of acetyl-CoA-derived chemicals were similar to those of arcA knockout in our previous study. However, the arcA-iclR double mutants couldn't gain higher productions of PG and 3HP. The mechanisms are unclear and needed to be resolved in future. Knockout of iclR significantly increased gene expression of aceBAK operon and concomitantly activated glyoxylate pathway. This genetic modification may be a good way to overcome acetate overflow, and improve the production of a wide range of acetyl-CoA-derived chemicals.

Mitomycin C and decarbamoyl mitomycin C induce p53-independent p21WAF1/CIP1 activation

PubMed Central

Cheng, Shu-Yuan; Seo, Jiwon; Huang, Bik Tzu; Napolitano, Tanya; Champeil, Elise

2016-01-01

Mitomycin C (MC), a commonly used anticancer drug, induces DNA damage via DNA alkylation. Decarbamoyl mitomycin C (DMC), another mitomycin lacking the carbamate at C10, generates similar lesions as MC. Interstrand cross-links (ICLs) are believed to be the lesions primarily responsible for the cytotoxicity of MC and DMC. The major ICL generated by MC (α-ICL) has a trans stereochemistry at the guanine-drug linkage whereas the major ICL from DMC (β-ICL) has the opposite, cis, stereochemistry. In addition, DMC can provoke strong p53-independent cell death. Our hypothesis is that the stereochemistry of the major unique β-ICL generated by DMC is responsible for this p53-independent cell death signaling. p53 gene is inactively mutated in more than half of human cancers. p21WAF1/CIP1 known as a major effector of p53 is involved in p53-dependent and -independent control of cell proliferation and death. This study revealed the role of p21WAF1/CIP1 on MC and DMC triggered cell damage. MCF-7 (p53-proficient) and K562 (p53-deficient) cells were used. Cell cycle distributions were shifted to the G1/S phase in MCF-7 treated with MC and DMC, but were shifted to the S phase in K562. p21WAF1/CIP1 activation was observed in both cells treated with MC and DMC, and DMC triggered more significant activation. Knocking down p53 in MCF-7 did not attenuate MC and DMC induced p21WAF1/CIP1 activation. The α-ICL itself was enough to cause p21WAF1/CIP1 activation. PMID:27666201

High-Speed Stark Wavelength Tuning of MidIR Interband Cascade Lasers

DTIC Science & Technology

2007-03-15

STARK WAVELENGTH TUNING OF MidIR ICLs 361 Fig. 2. Lasing spectra of the tunable ICL at different bias currents. injection region at before tunneling ...the energy separation between and (and hence the emission wavelength) undergoes a linear Stark shift that depends on the bias current which controls...response Fig. 3. Lasing spectra of the tunable ICL at different bias modulation frequen- cies. Fig. 4. Dependence of the intensity of the Line 2 on bias

The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross-Links in a Four-Stranded DNA Structure.

PubMed

Martin, Peter R; Couvé, Sophie; Zutterling, Caroline; Albelazi, Mustafa S; Groisman, Regina; Matkarimov, Bakhyt T; Parsons, Jason L; Elder, Rhoderick H; Saparbaev, Murat K

2017-12-12

Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA via hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from Xenopus laevis has been shown to cleave psoralen- and abasic site-induced ICLs in Xenopus egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct. Furthermore, while Nei and NEIL1 also cleave a psoralen-induced four-stranded DNA substrate to generate two unhooked DNA duplexes with a nick, NEIL3 targets both DNA strands in the ICL without generating single-strand breaks. The DNA substrate specificities of these Nei-like enzymes imply the occurrence of long uninterrupted three- and four-stranded crosslinked DNA-DNA structures that may originate in vivo from DNA replication fork bypass of an ICL. In conclusion, the Nei-like DNA glycosylases unhook psoralen-derived ICLs in various DNA structures via a genuine repair mechanism in which complex DNA lesions can be removed without generation of highly toxic double-strand breaks.

Limits of application of initiated chemiluminescence in monitoring of oncological process of mucous membrane of mouth and larynx.

PubMed

Oliynyk, Iryna

2016-09-01

Investigation into the limits of application of chemiluminescence (CL) methods in oncology still attracts the attention of researchers. In the present work we analyze the screening and monitoring of oncological processes (OP) in the mucous membrane of the mouth and larynx by initiated CL (ICL). Chemiluminescence has already been used by stomatologists to define the start of OP, but methods that reflect the metabolic changes in organism under cancer diagnostics still have not found their place. This work presents results of ICL on blood serum (BS) of patients with oncological diseases at different stages of medical treatment compared with those of healthy people. We found an essential metabolic difference only in types of OP that are characterized by two maxima on chemiluminograms. These OP represent only 12.81% of groups of patients with oncological diseases. The possibility to apply ICL methods to monitor operation quality and control medical treatment at different stages when the two ICL maxima are present is established. At present, the chemiluminograms with the two maxima are mostly informative, but this does not exclude the quantitative analysis of other ICL kinetic methods and is encouraging for their investigation. Any OP introduces changes in organism function and these should be reflected in the ICL. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

ABC transporter Cdr1p harbors charged residues in the intracellular loop and nucleotide-binding domain critical for protein trafficking and drug resistance.

PubMed

Shah, Abdul Haseeb; Banerjee, Atanu; Rawal, Manpreet Kaur; Saxena, Ajay Kumar; Mondal, Alok Kumar; Prasad, Rajendra

2015-08-01

The ABC transporter Cdr1 protein of Candida albicans, which plays a major role in antifungal resistance, has two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). The 12 transmembrane helices of TMDs that are interconnected by extracellular and intracellular loops (ICLs) mainly harbor substrate recognition sites where drugs bind while cytoplasmic NBDs hydrolyze ATP which powers drug efflux. The coupling of ATP hydrolysis to drug transport requires proper communication between NBDs and TMDs typically accomplished by ICLs. This study examines the role of cytoplasmic ICLs of Cdr1p by rationally predicting the critical residues on the basis of their interatomic distances. Among nine pairs that fall within a proximity of <4 Å, an ion pair between K577 of ICL1 and E315 of NBD1 was found to be critical. The substitution, swapping and changing of the length or charge of K577 or E315 by directed mutagenesis led to a misfolded, non-rescuable protein entrapped in intracellular structures. Furthermore, the equipositional ionic pair-forming residues from ICL3 and NBD2 (R1260 and E1014) did not impact protein trafficking. These results point to a new role for ICL/NBD interacting residues in PDR ABC transporters in protein folding and trafficking. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Epistatic role of base excision repair and mismatch repair pathways in mediating cisplatin cytotoxicity

PubMed Central

Kothandapani, Anbarasi; Sawant, Akshada; Dangeti, Venkata Srinivas Mohan Nimai; Sobol, Robert W.; Patrick, Steve M.

2013-01-01

Base excision repair (BER) and mismatch repair (MMR) pathways play an important role in modulating cis-Diamminedichloroplatinum (II) (cisplatin) cytotoxicity. In this article, we identified a novel mechanistic role of both BER and MMR pathways in mediating cellular responses to cisplatin treatment. Cells defective in BER or MMR display a cisplatin-resistant phenotype. Targeting both BER and MMR pathways resulted in no additional resistance to cisplatin, suggesting that BER and MMR play epistatic roles in mediating cisplatin cytotoxicity. Using a DNA Polymerase β (Polβ) variant deficient in polymerase activity (D256A), we demonstrate that MMR acts downstream of BER and is dependent on the polymerase activity of Polβ in mediating cisplatin cytotoxicity. MSH2 preferentially binds a cisplatin interstrand cross-link (ICL) DNA substrate containing a mismatch compared with a cisplatin ICL substrate without a mismatch, suggesting a novel mutagenic role of Polβ in activating MMR in response to cisplatin. Collectively, these results provide the first mechanistic model for BER and MMR functioning within the same pathway to mediate cisplatin sensitivity via non-productive ICL processing. In this model, MMR participation in non-productive cisplatin ICL processing is downstream of BER processing and dependent on Polβ misincorporation at cisplatin ICL sites, which results in persistent cisplatin ICLs and sensitivity to cisplatin. PMID:23761438

An initial reliability and validity study of the Interaction, Communication, and Literacy Skills Audit.

PubMed

El-Choueifati, Nisrine; Purcell, Alison; McCabe, Patricia; Heard, Robert; Munro, Natalie

2014-06-01

Early childhood educators (ECEs) have an important role in promoting positive outcomes for children's language and literacy development. This paper reports the development of a new tool, The Interaction Communication and Literacy (ICL) Skills Audit, and pilots its reliability and validity. Intra- and inter-rater reliability was examined by three speech-language pathologists (SLPs). Five skill areas relating to ECE language and literacy practice were rated. The face and content validity of the ICL Skills Audit was examined by expert SLPs (n = 8) and expert ECEs (n = 4) via questionnaire. The overall intra-rater reliability for the ICL Skills Audit was excellent with percentage close agreement (PCA) of 91-94. Inter-rater agreement was PCA 68-80. Expert SLPs and ECEs agreed that the content was comprehensive and practical. Based on this preliminary study, the ICL Skills Audit appears to be a promising tool that can be used by SLPs and ECEs in collaboration to measure the skills of ECEs in the areas of language and literacy support. Future psychometric and outcome research on the revised ICL Skills Audit is warranted.

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

PubMed Central

Eoh, Hyungjin; Rhee, Kyu Y.

2014-01-01

Few mutations attenuate Mycobacterium tuberculosis (Mtb) more profoundly than deletion of its isocitrate lyases (ICLs). However, the basis for this attenuation remains incompletely defined. Mtb’s ICLs are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids. Here, we report that Mtb’s ICLs are essential for survival on both acetate and propionate because of its methylisocitrate lyase (MCL) activity. Lack of MCL activity converts Mtb’s methylcitrate cycle into a “dead end” pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH. Activation of an alternative vitamin B12-dependent pathway of propionate metabolism led to selective corrections of TCA cycle activity, membrane potential, and intrabacterial pH that specifically restored survival, but not growth, of ICL-deficient Mtb metabolizing acetate or propionate. These results thus resolve the biochemical basis of essentiality for Mtb’s ICLs and survival on fatty acids. PMID:24639517

Development and Evaluation of a Pedagogical Tool to Improve Understanding of a Quality Checklist: A Randomised Controlled Trial

PubMed Central

Fourcade, Lola; Boutron, Isabelle; Moher, David; Ronceray, Lucie; Baron, Gabriel; Ravaud, Philippe

2007-01-01

Objective: The aim of this study was to develop and evaluate a pedagogical tool to enhance the understanding of a checklist that evaluates reports of nonpharmacological trials (CLEAR NPT). Design: Paired randomised controlled trial. Participants: Clinicians and systematic reviewers. Interventions: We developed an Internet-based computer learning system (ICLS). This pedagogical tool used many examples from published randomised controlled trials to demonstrate the main coding difficulties encountered when using this checklist. Randomised participants received either a specific Web-based training with the ICLS (intervention group) or no specific training. Outcome measures: The primary outcome was the rate of correct answers compared to a criterion standard for coding a report of randomised controlled trials with the CLEAR NPT. Results: Between April and June 2006, 78 participants were randomly assigned to receive training with the ICLS (39) or no training (39). Participants trained by the ICLS did not differ from the control group in performance on the CLEAR NPT. The mean paired difference and corresponding 95% confidence interval was 0.5 (−5.1 to 6.1). The rate of correct answers did not differ between the two groups regardless of the CLEAR NPT item. Combining both groups, the rate of correct answers was high or items related to allocation sequence (79.5%), description of the intervention (82.0%), blinding of patients (79.5%), and follow-up schedule (83.3%). The rate of correct answers was low for items related to allocation concealment (46.1%), co-interventions (30.3%), blinding of outcome assessors (53.8%), specific measures to avoid ascertainment bias (28.6%), and intention-to-treat analysis (60.2%). Conclusions: Although we showed no difference in effect between the intervention and control groups, our results highlight the gap in knowledge and urgency for education on important aspects of trial conduct. PMID:17479163

The Burrell Schmidt Deep Virgo Survey: Tidal Debris, Galaxy Halos, and Diffuse Intracluster Light in the Virgo Cluster

NASA Astrophysics Data System (ADS)

Mihos, J. Christopher; Harding, Paul; Feldmeier, John J.; Rudick, Craig; Janowiecki, Steven; Morrison, Heather; Slater, Colin; Watkins, Aaron

2017-01-01

We present the results of a deep imaging survey of the Virgo cluster of galaxies, concentrated around the cores of Virgo subclusters A and B. The goal of this survey was to detect and study very low surface brightness features present in Virgo, including discrete tidal features, the faint halos of luminous galaxies, and the diffuse intracluster light (ICL). Our observations span roughly 16 degrees2 in two filters, reaching a 3σ limiting depth of {μ }B = 29.5 and {μ }V = 28.5 mag arcsec-2. At these depths, our limiting systematic uncertainties are astrophysical: variations in faint background sources as well as scattered light from galactic dust. We show that this dust-scattered light is well traced by deep far-infrared imaging, making it possible to separate it from true diffuse light in Virgo. We use our imaging to trace and measure the color of the diffuse tidal streams and ICL in the Virgo core near M87, in fields adjacent to the core including the M86/M84 region, and to the south of the core around M49 and subcluster B, along with the more distant W{}\\prime cloud around NGC 4365. Overall, the bulk of the projected ICL is found in the Virgo core and within the W{}\\prime cloud; we find little evidence for an extensive ICL component in the field around M49. The bulk of the ICL we detect is fairly red in color (B - V = 0.7-0.9), indicative of old, evolved stellar populations. Based on the luminosity of the observed ICL features in the cluster, we estimate a total Virgo ICL fraction of 7%-15%. This value is somewhat smaller than that expected for massive, evolved clusters, suggesting that Virgo is still in the process of growing its extended ICL component. We also trace the shape of M87's extremely boxy outer halo out to ˜150 kpc, and show that the current tidal stripping rate from low luminosity galaxies is insufficient to have built M87's outer halo over a Hubble time. We identify a number of previously unknown low surface brightness structures around galaxies projected close to M86 and M84. The extensive diffuse light seen in the infalling W{}\\prime cloud around NGC 4365 is likely to be subsumed in the general Virgo ICL component once the group enters the cluster, illustrating the importance of group infall in generating ICL. Finally, we also identify another large and extremely low surface brightness ultradiffuse galaxy, likely in the process of being shredded by the cluster tidal field. With the survey complete, the full imaging data set is now available for public release.

Control of apical membrane chloride permeability in the renal A6 cell line by nucleotides

PubMed Central

Banderali, U; Brochiero, E; Lindenthal, S; Raschi, C; Bogliolo, S; Ehrenfeld, J

1999-01-01

The effect of extracellular nucleotides applied on the apical side of polarised A6 cells grown on permeant filters was investigated by measuring the changes in (i) the 36Cl efflux through the apical membranes, (ii) the intracellular chloride concentrations (aCli, measured with N-(6-methoxyquinolyl) acetoethyl ester, MQAE), (iii) ICl, the short-circuit current in the absence of Na+ transport and (iv) the characteristics of the apical chloride channels using a patch-clamp approach. ATP or UTP (0.1-500 μm) transiently stimulated ICl. The sequence of purinergic agonist potencies was UTP = ATP > ADP >> the P2X-selective agonist β,γ-methylene ATP = the P2Y-selective agonist 2-methylthioATP. Suramin (100 μm) as the P2Y antagonist Reactive Blue 2 (10 μm) had no effect on the UTP (or ATP)-stimulated current. These findings are consistent with the presence of P2Y2-like receptors located on the apical membranes of A6 cells. Apical application of adenosine also transiently increased ICl. This effect was blocked by theophylline while the UTP-stimulated ICl was not. The existence of a second receptor, of the P1 type is proposed. ATP (or UTP)-stimulated ICl was blocked by apical application of 200 μmN-phenylanthranilic acid (DPC) or 100 μm niflumic acid while 100 μm glibenclamide was ineffective. Ionomycin and thapsigargin both transiently stimulated ICl; the nucleotide stimulation of ICl was not suppressed by pre-treatment with these agents. Chlorpromazin (50 μm), a Ca2+-calmodulin inhibitor strongly inhibited the stimulation of ICl induced either by apical UTP or by ionomycin application. BAPTA-AM pre-treatment of A6 cells blocked the UTP-stimulated ICl. Niflumic acid also blocked the ionomycin stimulated ICl. A fourfold increase in 36Cl effluxes through the apical membranes was observed after ATP or UTP application. These increases of the apical chloride permeability could also be observed when following aCli changes. Apical application of DPC (1 mm) or 5-nitro-2(3-phenylpropylamino)benzoic acid (NPPB; 500 μm) produced an incomplete inhibition of 36Cl effluxes through the apical membranes in ATP-stimulated and in untreated monolayers. In single channel patch-clamp experiments, an apical chloride channel with a unitary single channel conductance of 7.3 ± 0.6 pS (n = 12) was usually observed. ATP application induced the activation of one or more of these channels within a few minutes. These results indicate that multiple purinergic receptor subtypes are present in the apical membranes of A6 cells and that nucleotides can act as modulators of Cl− secretion in renal cells. PMID:10457087

The Fanconi anaemia pathway: new players and new functions.

PubMed

Ceccaldi, Raphael; Sarangi, Prabha; D'Andrea, Alan D

2016-06-01

The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. The Fanconi anaemia pathway uses components of other known DNA repair processes to achieve proper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance.

Electronic properties of Al xGa 1- xAs surface passivated by ultrathin silicon interface control layer

NASA Astrophysics Data System (ADS)

Adamowicz, B.; Miczek, M.; Ikeya, K.; Mutoh, M.; Saitoh, T.; Fujikura, H.; Hasegawa, H.

1999-03-01

The photoluminescence surface state spectroscopy (PLS 3) method was applied to a study of the surface state distribution ( NSS), effective surface recombination velocity ( Seff), electron ( EFn) and hole ( EFp) quasi-Fermi levels and band bending ( VS) on the Al 0.33Ga 0.67As surface air-exposed and passivated by the Si interface control layer (ICL) technique. Using the detailed measurements of the PL quantum efficiency for different excitation intensities, combined with the rigorous computer simulations of the bulk and surface recombination processes, the behavior and correlation among the surface characteristics under photo-excitation was determined. The present analysis indicated that forming of a Si 3N 4/Si ICL double layer (with a monolayer level control) on AlGaAs surface reduces the minimum interface state density down to 10 10 cm -2 eV -1 and surface recombination velocity to the range of 10 4 cm/s under low excitations.

Force-induced rupture of double-stranded DNA in the absence and presence of covalently bonded anti-tumor drugs: Insights from molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Upadhyaya, Anurag; Nath, Shesh; Kumar, Sanjay

2018-06-01

DNA intra-strand cross-link (ICL) agents are widely used in the treatment of cancer. ICLs are thought to form a link between the same strand (intra-strand) or complimentary strand (inter-strand) and thereby increase the stability of DNA, which forbids the processes like replication and transcription. As a result, cell death occurs. In this work, we have studied the enhanced stability of a double stranded DNA in the presence of ICLs and compared our findings with the results obtained in the absence of these links. Using atomistic simulations with explicit solvent, a force is applied along and perpendicular to the direction of the helix and we measured the rupture force and the unzipping force of DNA-ICL complexes. Our results show that the rupture and the unzipping forces increase significantly in the presence of these links. The ICLs bind to the minor groove of DNA, which enhance the DNA stabilisation. Such information may be used to design alternative drugs that can stall replication and transcription that are critical to a growing number of anticancer drug discovery efforts.

Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling.

PubMed

Nikolova, Teodora; Roos, Wynand P; Krämer, Oliver H; Strik, Herwig M; Kaina, Bernd

2017-08-01

Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy. However, tumor cells resist chemotherapy through the repair of CNU-induced DNA damage. The suicide enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O 6 -chloroethylguanine prior to its conversion into ICL. In cells lacking MGMT, the formed ICL evoke complex enzymatic networks to accomplish their removal. Here we discuss the mechanism of ICL repair as a survival strategy of healthy and cancer cells and DNA damage signaling as a mechanism contributing to CNU-induced cell death. We also discuss therapeutic implications and strategies based on sequential and simultaneous treatment with CNU and the methylating drug temozolomide. Copyright © 2017 Elsevier B.V. All rights reserved.

Diffuse Optical Intracluster Light as a Measure of Stellar Tidal Stripping: The Cluster CL0024+17 at z ~ 0.4 Observed at the Large Binocular Telescope

NASA Astrophysics Data System (ADS)

Giallongo, E.; Menci, N.; Grazian, A.; Gallozzi, S.; Castellano, M.; Fiore, F.; Fontana, A.; Pentericci, L.; Boutsia, K.; Paris, D.; Speziali, R.; Testa, V.

2014-01-01

We have evaluated the diffuse intracluster light (ICL) in the central core of the galaxy cluster CL0024+17 at z ~ 0.4 observed with the prime focus camera (Large Binocular Camera) at the Large Binocular Telescope. The measure required an accurate removal of the galaxies' light within ~200 kpc from the center. The residual background intensity has then been integrated in circular apertures to derive the average ICL intensity profile. The latter shows an approximate exponential decline as expected from theoretical cold dark matter models where the ICL is due to the integrated contribution of light from stars that are tidally stripped from the halo of their host galaxies due to encounters with other galaxies in the cluster cold dark matter (CDM) potential. The radial profile of the ICL over the galaxies intensity ratio (ICL fraction) is increasing with decreasing radius, but near the cluster center it starts to bend and then decreases where the overlap of the halos of the brightest cluster galaxies becomes dominant. Theoretical expectations in a simplified CDM scenario show that the ICL fraction profile can be estimated from the stripped over galaxy stellar mass ratio in the cluster. It is possible to show that the latter quantity is almost independent of the properties of the individual host galaxies but mainly depends on the average cluster properties. The predicted ICL fraction profile is thus very sensitive to the assumed CDM profile, total mass, and concentration parameter of the cluster. Adopting values very similar to those derived from the most recent lensing analysis in CL0024+17, we find a good agreement with the observed ICL fraction profile. The galaxy counts in the cluster core have then been compared with that derived from composite cluster samples in larger volumes, up to the clusters virial radius. The galaxy counts in the CL0024+17 core appear flatter and the amount of bending with respect to the average cluster galaxy counts imply a loss of total emissivity in broad agreement with the measured ICL fraction. The present analysis shows that the measure of the ICL fraction in clusters can quantitatively account for the stellar stripping activity in their cores and can be used to probe their CDM distribution and evolutionary status. Observations have been carried out using the Large Binocular Telescope at Mt. Graham, AZ. The LBT is an international collaboration among institutions in the United States, Italy, and Germany. LBT Corporation partners are the University of Arizona on behalf of the Arizona university system; Istituto Nazionale di Astrofisica, Italy; LBT Beteiligungsgesellschaft, Germany, representing the Max-Planck Society, the Astrophysical Institute Potsdam, and Heidelberg University; the Ohio State University; and The Research Corporation, on behalf of the University of Notre Dame, University of Minnesota, and University of Virginia.

Meta-analysis and review: effectiveness, safety, and central port design of the intraocular collamer lens

PubMed Central

Packer, Mark

2016-01-01

The purpose of this review is to summarize relevant data from publications appearing in the peer-reviewed scientific literature over the past decade since US Food and Drug Administration approval of the implantable collamer lens (ICL), and, in particular, to review studies relating to sizing methodology, safety, and effectiveness, as well as more recent studies reporting clinical outcomes of the V4c Visian ICL with KS Aquaport, VICMO. A literature search was conducted using two databases, PubMed.gov and Science.gov, to identify all articles published after 2005 related to the Visian ICL (STAAR Surgical, Inc.). Articles were examined for their relevance to sizing methodology, clinical safety, and effectiveness, and the references cited in each article were also searched for additional relevant publications. The literature review revealed that all currently reported methods of determining the best-fit size of the ICL achieve similarly satisfactory results in terms of vault, the safe distance between the crystalline lens and the ICL. Specifically, meta-analysis demonstrated that sulcus-to-sulcus and white-to-white measurement-based sizing methods do not result in clinically meaningful nor statistically significant differences in vault (two-sample two-sided t-test using pooled mean and standard deviations; t (2,594)=1.33; P=0.18). The reported rates of complications related to vault are very low, except in two case series where additional risk factors such as higher levels of myopia and older age impacted the incidence of cataract. On the basis of preclinical studies and initial clinical reports, with up to 5 years of follow-up, the new VICMO central port design holds promise for further reduction of complications. Given its safety record and the significant improvement in vision and quality of life that the ICL makes possible, the benefits of ICL implantation outweigh the risks. PMID:27354760

Meta-analysis and review: effectiveness, safety, and central port design of the intraocular collamer lens.

PubMed

Packer, Mark

2016-01-01

The purpose of this review is to summarize relevant data from publications appearing in the peer-reviewed scientific literature over the past decade since US Food and Drug Administration approval of the implantable collamer lens (ICL), and, in particular, to review studies relating to sizing methodology, safety, and effectiveness, as well as more recent studies reporting clinical outcomes of the V4c Visian ICL with KS Aquaport, VICMO. A literature search was conducted using two databases, PubMed.gov and Science.gov, to identify all articles published after 2005 related to the Visian ICL (STAAR Surgical, Inc.). Articles were examined for their relevance to sizing methodology, clinical safety, and effectiveness, and the references cited in each article were also searched for additional relevant publications. The literature review revealed that all currently reported methods of determining the best-fit size of the ICL achieve similarly satisfactory results in terms of vault, the safe distance between the crystalline lens and the ICL. Specifically, meta-analysis demonstrated that sulcus-to-sulcus and white-to-white measurement-based sizing methods do not result in clinically meaningful nor statistically significant differences in vault (two-sample two-sided t-test using pooled mean and standard deviations; t (2,594)=1.33; P=0.18). The reported rates of complications related to vault are very low, except in two case series where additional risk factors such as higher levels of myopia and older age impacted the incidence of cataract. On the basis of preclinical studies and initial clinical reports, with up to 5 years of follow-up, the new VICMO central port design holds promise for further reduction of complications. Given its safety record and the significant improvement in vision and quality of life that the ICL makes possible, the benefits of ICL implantation outweigh the risks.

Chloride currents from the transverse tubular system in adult mammalian skeletal muscle fibers

PubMed Central

DiFranco, Marino; Herrera, Alvaro

2011-01-01

Chloride fluxes are the main contributors to the resting conductance of mammalian skeletal muscle fibers. ClC-1, the most abundant chloride channel isoform in this preparation, is believed to be responsible for this conductance. However, the actual distribution of ClC-1 channels between the surface and transverse tubular system (TTS) membranes has not been assessed in intact muscle fibers. To investigate this issue, we voltageclamped enzymatically dissociated short fibers using a two-microelectrode configuration and simultaneously recorded chloride currents (ICl) and di-8-ANEPPS fluorescence signals to assess membrane potential changes in the TTS. Experiments were conducted in conditions that blocked all but the chloride conductance. Fibers were equilibrated with 40 or 70 mM intracellular chloride to enhance the magnitude of inward ICl, and the specific ClC-1 blocker 9-ACA was used to eliminate these currents whenever necessary. Voltage-dependent di-8-ANEPPS signals and ICl acquired before (control) and after the addition of 9-ACA were comparatively assessed. Early after the onset of stimulus pulses, di-8-ANEPPS signals under control conditions were smaller than those recorded in the presence of 9-ACA. We defined as attenuation the normalized time-dependent difference between these signals. Attenuation was discovered to be ICl dependent since its magnitude varied in close correlation with the amplitude and time course of ICl. While the properties of ICl, and those of the attenuation seen in optical records, could be simultaneously predicted by model simulations when the chloride permeability (PCl) at the surface and TTS membranes were approximately equal, the model failed to explain the optical data if PCl was precluded from the TTS membranes. Since the ratio between the areas of TTS membranes and the sarcolemma is large in mammalian muscle fibers, our results demonstrate that a significant fraction of the experimentally recorded ICl arises from TTS contributions. PMID:21149546

Diffuse Optical Light in Galaxy Clusters. I. Abell 3888

NASA Astrophysics Data System (ADS)

Krick, J. E.; Bernstein, R. A.; Pimbblet, K. A.

2006-01-01

We are undertaking a program to measure the characteristics of the intracluster light (ICL; total flux, profile, color, and substructure) in a sample of 10 galaxy clusters with a range of cluster mass, morphology, and redshift. We present here the methods and results for the first cluster in that sample, A3888. We have identified an ICL component in A3888 in V and r that contains 13%+/-5% of the total cluster light and extends to 700 h-170 kpc (~0.3r200) from the center of the cluster. The ICL color in our smallest radial bin is V-r=0.3+/-0.1, similar to the central cluster elliptical galaxies. The ICL is redder than the galaxies at 400 h-170 kpc1) with a high-metallicity (1.0 Zsolar

Diffuse Optical Light in Galaxy Clusters. II. Correlations with Cluster Properties

NASA Astrophysics Data System (ADS)

Krick, J. E.; Bernstein, R. A.

2007-08-01

We have measured the flux, profile, color, and substructure in the diffuse intracluster light (ICL) in a sample of 10 galaxy clusters with a range of mass, morphology, redshift, and density. Deep, wide-field observations for this project were made in two bands at the 1 m Swope and 2.5 m du Pont telescopes at Las Campanas Observatory. Careful attention in reduction and analysis was paid to the illumination correction, background subtraction, point-spread function determination, and galaxy subtraction. ICL flux is detected in both bands in all 10 clusters ranging from 7.6×1010 to 7.0×1011 h-170 Lsolar in r and 1.4×1010 to 1.2×1011 h-170 Lsolar in the B band. These fluxes account for 6%-22% of the total cluster light within one-quarter of the virial radius in r and 4%-21% in the B band. Average ICL B-r colors range from 1.5 to 2.8 mag when k- and evolution corrected to the present epoch. In several clusters we also detect ICL in group environments near the cluster center and up to 1 h-170 Mpc distant from the cluster center. Our sample, having been selected from the Abell sample, is incomplete in that it does not include high-redshift clusters with low density, low flux, or low mass, and it does not include low-redshift clusters with high flux, high mass, or high density. This bias makes it difficult to interpret correlations between ICL flux and cluster properties. Despite this selection bias, we do find that the presence of a cD galaxy corresponds to both centrally concentrated galaxy profiles and centrally concentrated ICL profiles. This is consistent with ICL either forming from galaxy interactions at the center or forming at earlier times in groups and later combining in the center.

Soil organic carbon assessments in cropping systems using isotopic techniques

NASA Astrophysics Data System (ADS)

Martín De Dios Herrero, Juan; Cruz Colazo, Juan; Guzman, María Laura; Saenz, Claudio; Sager, Ricardo; Sakadevan, Karuppan

2016-04-01

Introduction of improved farming practices are important to address the challenges of agricultural production, food security, climate change and resource use efficiency. The integration of livestock with crops provides many benefits including: (1) resource conservation, (2) ecosystem services, (3) soil quality improvements, and (4) risk reduction through diversification of enterprises. Integrated crop livestock systems (ICLS) with the combination of no-tillage and pastures are useful practices to enhance soil organic carbon (SOC) compared with continuous cropping systems (CCS). In this study, the SOC and its fractions in two cropping systems namely (1) ICLS, and (2) CCS were evaluated in Southern Santa Fe Province in Argentina, and the use of delta carbon-13 technique and soil physical fractionation were evaluated to identify sources of SOC in these systems. Two farms inside the same soil cartographic unit and landscape position in the region were compared. The ICLS farm produces lucerne (Medicago sativa Merrill) and oat (Avena sativa L.) grazed by cattle alternatively with grain summer crops sequence of soybean (Glicine max L.) and corn (Zea mays L.), and the farm under continuous cropping system (CCS) produces soybean and corn in a continuous sequence. The soil in the area is predominantly a Typic Hapludoll. Soil samples from 0-5 and 0-20 cm depths (n=4) after the harvest of grain crops were collected in each system and analyzed for total organic carbon (SOC, 0-2000 μm), particulate organic carbon (POC, 50-100 μm) and mineral organic carbon (MOC, <50 μm). Delta carbon-13 was determined by isotopic ratio mass spectrometry. In addition, a site with natural vegetation (reference site, REF) was also sampled for delta carbon-13 determination. ANOVA and Tukey statistical analysis were carried out for all data. The SOC was higher in ICLS than in CCS at both depths (20.8 vs 17.7 g kg-1 for 0-5 cm and 16.1 vs 12.7 g kg-1 at 0-20 cm, respectively, P<0.05). MOC was similar at both depths, and POC was higher in CCS than in ICLS at 0-5 cm, while at 0-20 cm this trend was opposite. This is probably due to the presence of deep roots under pastures in ICLS. Delta carbon-13 values for 0-5 cm were -22.9, -21.2 and -19.9 per mil for REF, ICLS and CCS, respectively (P<0.05). The lower delta carbon-13 in REF soils is explained by the presence of tree species with high lignin content in natural vegetation. Lignin has lower delta carbon-13 compared to cellulose (dominating in crops and pastures), which is present in greater proportion in plant residues of ICLS and CCS. Delta carbon-13 for 0-20 cm depth was similar for both systems. This means that in CCS there was a higher C input from C4 plants than in ICLS and REF, reflecting corn-plant residue contribution to SOC, meanwhile the main component of SOC in ICLS derived from pasture-plant residues. Results showed that ICLS under no tillage improved SOC levels due to higher plant residue inputs derived mainly from pasture compared to continuous cropping systems.

Lysine succinylation of Mycobacterium tuberculosis isocitrate lyase (ICL) fine-tunes the microbial resistance to antibiotics.

PubMed

Zhou, Mingliang; Xie, Longxiang; Yang, Zhaozhen; Zhou, Jiahai; Xie, Jianping

2017-04-01

Lysine succinylation (Ksucc) is a newly identified protein posttranslational modification (PTM), which may play an important role in cellular physiology. However, the role of lysine succinylation in antibiotic resistance remains elusive. Isocitrate lyase (ICL) is crucial for broad-spectrum antibiotics tolerance in Mycobacterium tuberculosis (Mtb). We previously found that MtbICL (Rv0467) has at least three succinylated lysine residues, namely K189, K322, and K334.To explore the effect of succinylation on the activity of MtbICL, mutants' mimicry of the lysine succinylation were generated by site-directed mutagenesis. ICL-K189E mutant strain is more sensitive than the wild-type to rifampicin and streptomycin, but not isoniazid. For the in vitro activity of the purified isocitrate lyase, only K189E mutant showed significantly decreased activity. Crystal structure analysis showed that Lys189 Glu dramatically increased the pKa of Glu188 and decreased the pKa of Lys190, whereas had negligible effect on other residues within 5 Å as well as disruption of the electrostatic interaction between Lys189 and Glu182, which might prevent the closure of the active site loop and cause severe reduction of the enzyme activity. Considering the genetic, biochemical, and crystallographical evidences together, the succinylation of specific ICL residue can fine-tune the bacterial resistance to selected antibiotics. The decreased enzymatic activity resulting from the succinylation-changed electrostatic interaction might underlie this phenotype. This study provided the first insight into the link between lysine succinylation and antibiotic resistance.

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation.

PubMed

Demuth, Ilja; Digweed, Martin; Concannon, Patrick

2004-11-11

DNA interstrand crosslinks (ICLs) are critical lesions for the mammalian cell since they affect both DNA strands and block transcription and replication. The repair of ICLs in the mammalian cell involves components of different repair pathways such as nucleotide-excision repair and the double-strand break/homologous recombination repair pathways. However, the mechanistic details of mammalian ICL repair have not been fully delineated. We describe here the complete coding sequence and the genomic organization of hSNM1B, one of at least three human homologs of the Saccharomyces cerevisiae PSO2 gene. Depletion of hSNM1B by RNA interference rendered cells hypersensitive to ICL-inducing agents. This requirement for hSNM1B in the cellular response to ICL has been hypothesized before but never experimentally verified. In addition, siRNA knockdown of hSNM1B rendered cells sensitive to ionizing radiation, suggesting the possibility of hSNM1B involvement in homologous recombination repair of double-strand breaks arising as intermediates of ICL repair. Monoubiquitination of FANCD2, a key step in the FANC/BRCA pathway, is not affected in hSNM1B-depleted HeLa cells, indicating that hSNM1B is probably not a part of the Fanconi anemia core complex. Nonetheless, similarities in the phenotype of hSNM1B-depleted cells and cultured cells from patients suffering from Fanconi anemia make hSNM1B a candidate for one of the as yet unidentified Fanconi anemia genes not involved in monoubiquitination of FANCD2.

A Census of Baryons in Galaxy Clusters and Groups

NASA Astrophysics Data System (ADS)

Gonzalez, Anthony H.; Zaritsky, Dennis; Zabludoff, Ann I.

2007-09-01

We determine the contribution of stars in galaxies, intracluster stars, and the intracluster medium to the total baryon budget in nearby galaxy clusters and groups. We find that the baryon mass fraction (fb≡Ωb/Ωm) within r500 is constant for systems with M500 between 6×1013 and 1×1015 Msolar. Although fb is lower than the WMAP value, the shortfall is on the order of both the observational systematic uncertainties and the depletion of baryons within r500 that is predicted by simulations. The data therefore provide no compelling evidence for undetected baryonic components, particularly any that would be expected to vary in importance with cluster mass. A unique feature of the current analysis is direct inclusion of the contribution of intracluster light (ICL) in the baryon budget. With the addition of the ICL to the stellar mass in galaxies, the increase in X-ray gas mass fraction with increasing total mass is entirely accounted for by a decrease in the total stellar mass fraction, supporting the argument that the behavior of both the stellar and X-ray gas components is dominated by a decrease in star formation efficiency in more massive environments. Within just the stellar component, the fraction of the total stellar luminosity in the central, giant brightest cluster galaxy (BCG) and ICL (hereafter the BCG+ICL component) decreases as velocity dispersion (σ) increases for systems with 145 km s-1<=σ<=1026 km s-1, suggesting that the BCG+ICL component, and in particular the dominant ICL component, grows less efficiently in higher mass environments. The degree to which this behavior arises from our sample selection, which favored systems with central, giant elliptical galaxies, remains unclear. A more robust result is the identification of low-mass groups with large BCG+ICL components, demonstrating that the creation of ``intracluster'' stars does not require a massive cluster environment. Within r500 and r200, the BCG+ICL contributes on average 40% and 33% of the total stellar light, respectively, for the clusters and groups in our sample. Because these fractions are functions of both enclosed radius and system mass, care should be exercised when comparing these values with other studies and simulations.

Clothing insulation and temperature, layer and mass of clothing under comfortable environmental conditions

PubMed Central

2013-01-01

This study was designed to investigate the relationship between the microclimate temperature and clothing insulation (Icl) under comfortable environmental conditions. In total, 20 subjects (13 women, 7 men) took part in this study. Four environmental temperatures were chosen: 14°C (to represent March/April), 25°C (May/June), 29°C (July/August), and 23°C (September/October). Wind speed (0.14ms-1) and humidity (45%) were held constant. Clothing microclimate temperatures were measured at the chest (Tchest) and on the interscapular region (Tscapular). Clothing temperature of the innermost layer (Tinnermost) was measured on this layer 30 mm above the centre of the left breast. Subjects were free to choose the clothing that offered them thermal comfort under each environmental condition. We found the following results. 1) All clothing factors except the number of lower clothing layers (Llower), showed differences between the different environmental conditions (P<0.05). The ranges of Tchest were 31.6 to 33.5°C and 32.2 to 33.4°C in Tscapular. The range of Tinnermost was 28.6 to 32.0°C. The range of the upper clothing layers (Lupper) and total clothing mass (Mtotal) was 1.1 to 3.2 layers and 473 to 1659 g respectively. The range of Icl was 0.78 to 2.10 clo. 2) Post hoc analyses showed that analysis of Tinnermost produced the same results as for that of Icl. Likewise, the analysis of Lupper produced the same result as the analysis of the number of total layers (Ltotal) within an outfit. 3) Air temperature (ta) had positive relationships with Tchest and Tscapular and with Tinnermost but had inverse correlations with Icl, Mtotal, Lupper and Ltotal. Tchest, Tscapular, and Tinnermost increased as ta rose. 4) Icl had inverse relationships with Tchest and Tinnermost, but positive relationships with Mtotal, Lupper and Ltotal. Icl could be estimated by Mtotal, Lupper, and Tscapular using a multivariate linear regression model. 5) Lupper had positive relationships with Icl and Mtotal, but Llower did not. Subjects hardly changed Llower under environmental comfort conditions between March and October. This indicates that each of the Tchest, Mtotal, and Lupper was a factor in predicting Icl. Tinnermost might also be a more influential factor than the clothing microclimate temperature. PMID:23816370

Assessing oxygen saturation in retinal vessels in high myopia patients pre- and post-implantable collamer lens implantation surgery.

PubMed

Chen, Pei; Cai, Xiaoxiao; Xu, Lijun; Zhang, Jing; Yang, Ying; Gao, Qianying; Ge, Jian; Yu, Keming; Zhuang, Jing

2017-09-01

To determine whether posterior chamber phakic implantable collamer lens (ICL) surgery in high myopia patients impedes oxygen saturation of retinal vessels. Mean oxygen saturation and diameter in retinal blood vessels were measured before and after ICL implantation surgery to correct high myopia refractive errors (i.e. -6.00 to -20.25 dioptres [D]), using an Oxymap T1 retinal oximeter. In 17 eyes of 17 patients, the Oxymap T1 retinal oximeter detected a small but significant decrease in oxygen saturation of retinal venules, 1-week postoperatively (compared to preoperative measurements). Moreover, at 1 week after ICL implantation, the diameter of patient retinal vessels had consistently contracted, compared to preoperative measurements. By 1 month after ICL surgery, however, both the oxygen saturation and retinal vessel diameter had returned to preoperative levels. Otherwise, no statistically significant difference in oxygen saturation and diameter of retinal arterioles was found when comparing their measurements before and 1 week after implantation. Stable levels of oxygen saturation in retinal vessels, as detected by the Oxymap T1 oximeter, show ICL implantation would not leave lasting impact or adverse effects to retina oxygen saturation in high myopia patients. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Weight, Length, and Body Mass Index Growth of Children Under 2 Years of Age With Cleft Lip and Palate.

PubMed

Miranda, Gabriela Serrano; Marques, Ilza Lazarini; de Barros, Suely Prietto; Arena, Eliane Petean; de Souza, Luiz

2016-05-01

To study the growth of length-for-age (L/A), weight-for-age (W/A), and body mass index (BMI) of children with cleft lip and palate receiving a normal diet; to establish specific growth curves for children with cleft palate with or without cleft lip (CLP/ICP) who had not undergone palatoplasty and for children with isolated cleft lip (ICL); and to assess if CLP/ICP growth differed from ICL growth and if CLP/ICP and ICL growth differed from growth for typical children. Prospective and cross-sectional study. Hospital for Rehabilitation of Craniofacial Anomalies, Bauru, São Paulo, Brazil. Weight and length of 381 children with cleft lip and palate and who were younger than 2 years were recorded and used to calculate W/A, L/A, and BMI growth curves. The 2006 World Health Organization growth charts were used as a reference for typical children. All children received a normal diet for age. Children with CLP/ICP had median W/A and BMI growth curves below growth curves for typical children but showed spontaneous recovery starting at approximately 5 months of age, even with nonoperated cleft palate. Children with ICL had growth similar to that of typical children. Children with CLP/ICP, who initially had W/A and BMI values less than those of the ICL group, had W/A and BMI equal to or higher than the ICL group after 9 months of age. Children with CLP/ICP had impaired W/A and BMI growth with spontaneous recovery starting early in childhood. This study established specific W/A, BMI, and L/A growth curves for children with cleft lip and palate.

Preparation and properties of pure, full-length IclR protein of Escherichia coli. Use of time-of-flight mass spectrometry to investigate the problems encountered.

PubMed Central

Donald, L. J.; Chernushevich, I. V.; Zhou, J.; Verentchikov, A.; Poppe-Schriemer, N.; Hosfield, D. J.; Westmore, J. B.; Ens, W.; Duckworth, H. W.; Standing, K. G.

1996-01-01

IclR protein, the repressor of the aceBAK operon of Escherichia coli, has been examined by time-of-flight mass spectrometry, with ionization by matrix assisted laser desorption or by electrospray. The purified protein was found to have a smaller mass than that predicted from the base sequence of the cloned iclR gene. Additional measurements were made on mixtures of peptides derived from IclR by treatment with trypsin and cyanogen bromide. They showed that the amino acid sequence is that predicted from the gene sequence, except that the protein has suffered truncation by removal of the N-terminal eight or, in some cases, nine amino acid residues. The peptide bond whose hydrolysis would remove eight residues is a typical target for the E. coli protease OmpT. We find that, by taking precautions to minimize Omp T proteolysis, or by eliminating it through mutation of the host strain, we can isolate full-length IclR protein (lacking only the N-terminal methionine residue). Full-length IclR is a much better DNA-binding protein than the truncated versions: it binds the aceBAK operator sequence 44-fold more tightly, presumably because of additional contacts that the N-terminal residues make with the DNA. Our experience thus demonstrates the advantages of using mass spectrometry to characterize newly purified proteins produced from cloned genes, especially where proteolysis or other covalent modification is a concern. This technique gives mass spectra from complex peptide mixtures that can be analyzed completely, without any fractionation of the mixtures, by reference to the amino acid sequence inferred from the base sequence of the cloned gene. PMID:8844850

Management of pseudophakic myopic anisometropic amblyopia with piggyback Visian® implantable collamer lens.

PubMed

Eissa, Sherif A

2017-03-01

To assess the outcomes of sulcus implantation of the Visian ® implantable collamer lens (ICL) to correct pseudophakic myopic anisometropic amblyopia with myopic shift and/or primary refractive overcorrection. Prospective case series enrolled 14 pseudophakic eyes of 14 patients, 5-9 years old, with history of cataract surgery and primary in the bag-intraocular lenses (IOL) implantation, followed by myopic shift and/or refractive overcorrection and anisometropic amblyopia of variable degrees. All cases had implantation of a piggyback ICL/toric ICL, to correct the myopia/myopic astigmatism. Preoperatively, we evaluated the uncorrected distance visual acuity (UCVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent (MRSE), intraocular pressure (IOP) and endothelial cell density (ECD). We assessed the position and vaulting of the ICLs on slit lamp examination and confirmed by Scheimpflug tomography. Postoperative follow-up was at 1st week and 1, 3, 6, 9, 12, 18 and 24 months. Uncorrected distance visual acuity improved in all cases, and CDVA improved in 11 amblyopic eyes (2-4 lines). There was no evidence of interlenticular opacification (ILO) throughout the 2-year follow-up. Two cases were complicated with early postoperative acute elevation of IOP and were controlled with topical beta-blockers. Postoperative acute anterior uveitis occurred in six eyes and controlled by topical steroids. Implantable collamer lens (ICL) vault was measured using Pentacam, with mean value of 470 ± 238 μm. Sulcus implantation of the secondary piggyback ICL to correct unilateral pseudophakic myopic refractive error in children was safe, efficient, predictable and well tolerated in management of anisometropic amblyopia in all eyes. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Advanced pigment dispersion glaucoma secondary to phakic intraocular collamer lens implant.

PubMed

Ye, Clara; Patel, Cajal K; Momont, Anna C; Liu, Yao

2018-06-01

We report a case of pigment dispersion glaucoma secondary to uncomplicated phakic intraocular collamer lens (ICL) (Visian ICL™, Staar Inc., Monrovia, CA) implant that resulted in advanced visual field loss. A 50-year-old man presented for routine follow-up status post bilateral phakic intraocular collamer lens (ICL) placement 8 years earlier. He was incidentally found to have a decline in visual acuity from an anterior subcapsular cataract and elevated intraocular pressure (IOP) in the left eye. There were signs of pigment dispersion and no evidence of angle closure. Diffuse optic nerve thinning was consistent with advanced glaucomatous visual field defects. Pigment dispersion was also present in the patient's right eye, but without elevated IOP or visual field defects. The patient was treated with topical glaucoma medications and the phakic ICL in the left eye was removed concurrently with cataract surgery to prevent further visual field loss. Pigment dispersion glaucoma is a serious adverse outcome after phakic ICL implantation and regular post-operative monitoring may prevent advanced visual field loss.

Distributed feedback interband cascade lasers with top grating and corrugated sidewalls

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xie, Feng; Stocker, Michael; Pham, John

Distributed feedback (DFB) interband cascade lasers (ICLs) with a 1st order top surface grating were designed and fabricated. Partially corrugated sidewalls were implemented to suppress high order lateral modes. The DFB ICLs have 4 mm long and 4.5 mu m wide ridge waveguides and are mounted epi-up on AlN submounts. We demonstrated a continuous-wave (CW) DFB ICL, from a first wafer which has a large detuning of the gain peak from the DFB wavelength, with a side mode suppression ratio of 30 dB. With proper matching of grating feedback and the gain peak wavelength for the second wafer, a DFBmore » ICL was demonstrated with a maximum CW output power and a maximum wall plug efficiency reaching 42 mW and 2%, respectively, at 25 degrees C. The lasing wavelengths of both lasers are around 3.3 mu m at 25 degrees C. Published by AIP Publishing.« less

[Long-term results of posterior chamber phakic intraocular lens implantation for correction of high ametropia].

PubMed

Le Loir, M; Cochener, B

2012-06-01

To assess efficacy, stability and safety of posterior chamber phakic intraocular lens implantation with STAAR Visian ICL for correction of high ametropia, with a mean follow-up of 5 years (3.5-10 years). Ninety eyes of 53 highly ametropic patients (45 myopia, ten hyperopia and 35 with mixed astigmatism) were included in a retrospective single-surgeon study, using primarily the V4 ICL model (87 eyes). We studied pre- and postoperative refractive efficacy, endothelial cell density, crystalline lens opacification and intraocular clearances within the various compartments of the eye. Mean uncorrected visual acuity was 0.77 at the 12th postoperative month; 17 of 90 eyes required adjunctive photoablation for residual astigmatism. Forty-eight percent of eyes gained at least one line of best corrected visual acuity. After implantation, the decrease in endothelial cell density remained stable at 0.69%/year, and 91% of eyes showed no opacification of the crystalline lens. Mean endothelium-ICL and ICL-crystalline lens distances were 2.41 mm and 0.52 mm respectively. Overall patient satisfaction achieved was 96% at 36 months postoperatively. These results demonstrate efficacy, stability and safety of the ICL V4 phakic IOL for the correction of high ametropia. Long-term follow-up did not show a significant increase in cataract formation in implanted eyes. Copyright © 2012. Published by Elsevier Masson SAS.

Positional and rotational stability of the toric phakic intraocular lens under high +Gz environments.

PubMed

Tan, Marcus C L; Nah, Gerard K M

2012-02-01

Phakic intraocular lens (PIOL) implantation is a surgical option for correction of refractive errors. PIOLs can be use to correct myopia, hyperopia, and astigmatism. It is a surgical option available to patients in addition to methods such as laser cornea refractive surgery, e.g., laser assisted in-situ keratomileusis (LASIK) and photo-refractive keratectomy (PRK). Visian implantable collamer lens (ICL) are posterior chamber lenses which are surgically positioned in a phakic eye in the sulcus between the iris diaphragm and the natural crystalline lens. This case report describes the stability of Visian toric ICL in a candidate with bilateral implants under high +Gz force exposure in a human centrifuge trainer. The subject was sequentially exposed to three incremental +Gz profiles of +5 Gz, +7 Gz, and +9 Gz. Pre- and post-+Gz exposure, ophthalmic examination revealed no ICL displacement, implant touch or induced cataract, or change in refractive error. The rotational stability of the toric implants was also demonstrated by identical subjective refractions in both eyes taken pre- and post-+Gz, exposure. A search of the literature did not reveal any published articles on intraocular stability of ICL in the +Gz environment. This case report suggests that ICL may be considered an alternative to laser refractive surgery for patients subjected to a high +G, environment such as military aviators.

Hormonal regulation of gluconeogenesis in cereal aleurone is strongly cultivar-dependent and gibberellin action involves SLENDER1 but not GAMYB.

PubMed

Eastmond, Peter J; Jones, Russell L

2005-11-01

Storage oil is a major constituent in the cereal aleurone layer. The aim of this study was to investigate how gibberellin (GA) and abscisic acid (ABA) regulate conversion of oil to sugar in barley aleurone. The activity of the glyoxylate cycle enzyme isocitrate lyase (ICL) was surveyed in eight barley cultivars. Surprisingly, some cultivars do not require GA for the induction of ICL (e.g. Himalaya), whereas some do (e.g. Golden Promise). Furthermore, in Golden Promise, GA also stimulates triacylglycerol breakdown and enhances the net flux of carbon from acetate to sugar. In contrast, ABA strongly represses ICL activity and the flux of carbon from oil to sugar in both Golden Promise and Himalaya. Biolistics using a promoter reporter showed that GA and ABA regulate ICL at the level of transcription. Studies using barley and rice mutants and pharmacological agents show that GA-dependent induction of ICL activity is mediated by SLENDER1 and requires cGMP, but does not involve the transcription factor GAMYB. Gibberellin and ABA therefore act antagonistically to regulate gluconeogenesis in the aleurone layer as well as controlling the production and secretion of hydrolases into the starchy endosperm. We suggest that the variation between different barley cultivars might be a result of selective breeding to alter seed dormancy.

Adapting a Navier-Stokes code to the ICL-DAP

NASA Technical Reports Server (NTRS)

Grosch, C. E.

1985-01-01

The results of an experiment are reported, i.c., to adapt a Navier-Stokes code, originally developed on a serial computer, to concurrent processing on the CL Distributed Array Processor (DAP). The algorithm used in solving the Navier-Stokes equations is briefly described. The architecture of the DAP and DAP FORTRAN are also described. The modifications of the algorithm so as to fit the DAP are given and discussed. Finally, performance results are given and conclusions are drawn.

Integrated crop-livestock system effects on soil N, P, and pH in a semiarid region

USDA-ARS?s Scientific Manuscript database

Integrated crop-livestock systems (ICLS) represent a potential means to sustainably intensify agriculture. Developing ICLS that concurrently achieve production and environmental goals is contingent upon efficiently managing plant nutrients in time and space. In this study, we sought to quantify re...

Photoluminescence and capacitance voltage characterization of GaAs surface passivated by an ultrathin GaN interface control layer

NASA Astrophysics Data System (ADS)

Anantathanasarn, Sanguan; Hasegawa, Hideki

2002-05-01

A novel surface passivation technique for GaAs using an ultrathin GaN interface control layer (GaN ICL) formed by surface nitridation was characterized by ultrahigh vacuum (UHV) photoluminescence (PL) and capacitance-voltage ( C- V) measurements. The PL quantum efficiency was dramatically enhanced after being passivated by the GaN ICL structure, reaching as high as 30 times of the initial clean GaAs surface. Further analysis of PL data was done by the PL surface state spectroscopy (PLS 3) simulation technique. PL and C- V results are in good agreement indicating that ultrathin GaN ICL reduces the gap states and unpins the Fermi level, realizing a wide movement of Fermi level within the midgap region and reduction of the effective surface recombination velocity by a factor of 1/60. GaN layer also introduced a large negative surface fixed charge of about 10 12 cm -2. A further improvement took place by depositing a Si 3N 4 layer on GaN ICL/GaAs structure.

DOG-1 Is the Caenorhabditis elegans BRIP1/FANCJ Homologue and Functions in Interstrand Cross-Link Repair▿

PubMed Central

Youds, Jillian L.; Barber, Louise J.; Ward, Jordan D.; Collis, Spencer J.; O'Neil, Nigel J.; Boulton, Simon J.; Rose, Ann M.

2008-01-01

Fanconi anemia (FA) is a cancer susceptibility syndrome characterized by defective DNA interstrand cross-link (ICL) repair. Here, we show that DOG-1 is the Caenorhabditis elegans homologue of FANCJ, a helicase mutated in FA-J patients. DOG-1 performs a conserved role in ICL repair, as dog-1 mutants are hypersensitive to ICL-inducing agents, but not to UVC irradiation or X rays. Genetic analysis indicated that dog-1 is epistatic with fcd-2 (C. elegans FANCD2) but is nonepistatic with brc-1 (C. elegans BRCA1), thus establishing the existence of two distinct pathways of ICL repair in worms. Furthermore, DOG-1 is dispensable for FCD-2 and RAD-51 focus formation, suggesting that DOG-1 operates downstream of FCD-2 and RAD-51 in ICL repair. DOG-1 was previously implicated in poly(G)/poly(C) (G/C) tract maintenance during DNA replication. G/C tracts remain stable in the absence of ATL-1, CLK-2 (FA pathway activators), FCD-2, BRC-2, and MLH-1 (associated FA components), implying that DOG-1 is the sole FA component required for G/C tract maintenance in a wild-type background. However, FCD-2 is required to promote deletion-free repair at G/C tracts in dog-1 mutants, consistent with a role for FA factors at the replication fork. The functional conservation between DOG-1 and FANCJ suggests a possible role for FANCJ in G/C tract maintenance in human cells. PMID:18086896

Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks.

PubMed

Mason, Jennifer M; Sekiguchi, JoAnn M

2011-07-01

Fanconi anemia (FA) is an inherited chromosomal instability disorder characterized by childhood aplastic anemia, developmental abnormalities and cancer predisposition. One of the hallmark phenotypes of FA is cellular hypersensitivity to agents that induce DNA interstrand crosslinks (ICLs), such as mitomycin C (MMC). FA is caused by mutation in at least 14 genes which function in the resolution of ICLs during replication. The FA proteins act within the context of a protein network in coordination with multiple repair factors that function in distinct pathways. SNM1B/Apollo is a member of metallo-β-lactamase/βCASP family of nucleases and has been demonstrated to function in ICL repair. However, the relationship between SNM1B and the FA protein network is not known. In the current study, we establish that SNM1B functions epistatically to the central FA factor, FANCD2, in cellular survival after ICL damage and homology-directed repair of DNA double-strand breaks. We also demonstrate that MMC-induced chromosomal anomalies are increased in SNM1B-depleted cells, and this phenotype is not further exacerbated upon depletion of either FANCD2 or another key FA protein, FANCI. Furthermore, we find that SNM1B is required for proper localization of critical repair factors, including FANCD2, BRCA1 and RAD51, to MMC-induced subnuclear foci. Our findings demonstrate that SNM1B functions within the FA pathway during the repair of ICL damage.

Fanconi Anemia Proteins, DNA Interstrand Crosslink Repair Pathways, and Cancer Therapy

PubMed Central

Andreassen, Paul R.; Ren, Keqin

2016-01-01

DNA interstrand crosslinkers, a chemically diverse group of compounds which also induce alkylation of bases and DNA intrastrand crosslinks, are extensively utilized for cancer therapy. Understanding the cellular response to DNA damage induced by these agents is critical for more effective utilization of these compounds and for the identification of novel therapeutic targets. Importantly, the repair of DNA interstrand crosslinks (ICLs) involves many distinct DNA repair pathways, including nucleotide excision repair, translesion synthesis (TLS), and homologous recombination (HR). Additionally, proteins implicated in the pathophysiology of the multigenic disease Fanconi anemia (FA) have a role in the repair of ICLs that is not well understood. Cells from FA patients are hypersensitive to agents that induce ICLs, therefore FA proteins are potentially novel therapeutic targets. Here we will review current research directed at identifying FA genes and understanding the function of FA proteins in DNA damage responses. We will also examine interactions of FA proteins with other repair proteins and pathways, including signaling networks, which are potentially involved in ICL repair. Potential approaches to the modulation of FA protein function to enhance therapeutic outcome will be discussed. Also, mutation of many genes that encode proteins involved in ICL repair, including FA genes, increases susceptibility to cancer. A better understanding of these pathways is therefore critical for the design of individualized therapies tailored to the genetic profile of a particular malignancy. For this purpose, we will also review evidence for the association of mutation of FA genes with cancer in non-FA patients. PMID:19200054

Integration of health services improves multiple healthcare outcomes among HIV-infected people who inject drugs in Ukraine.

PubMed

Bachireddy, Chethan; Soule, Michael C; Izenberg, Jacob M; Dvoryak, Sergey; Dumchev, Konstantin; Altice, Frederick L

2014-01-01

People who inject drugs (PWID) experience poor outcomes and fuel HIV epidemics in middle-income countries in Eastern Europe and Central Asia. We assess integrated/co-located (ICL) healthcare for HIV-infected PWID, which despite international recommendations, is neither widely available nor empirically examined. A 2010 cross-sectional study randomly sampled 296 HIV-infected opioid-dependent PWID from two representative HIV-endemic regions in Ukraine where ICL, non-co-located (NCL) and harm reduction/outreach (HRO) settings are available. ICL settings provide onsite HIV, addiction, and tuberculosis services, NCLs only treat addiction, and HROs provide counseling, needles/syringes, and referrals, but no opioid substitution therapy (OST). The primary outcome was receipt of quality healthcare, measured using a quality healthcare indicator (QHI) composite score representing percentage of eight guidelines-based recommended indicators met for HIV, addiction and tuberculosis treatment. The secondary outcomes were individual QHIs and health-related quality-of-life (HRQoL). On average, ICL-participants had significantly higher QHI composite scores compared to NCL- and HRO-participants (71.9% versus 54.8% versus 37.0%, p<0.001) even after controlling for potential confounders. Compared to NCL-participants, ICL-participants were significantly more likely to receive antiretroviral therapy (49.5% versus 19.2%, p<0.001), especially if CD4 ≤ 200 (93.8% versus 62.5% p<0.05); guideline-recommended OST dosage (57.3% versus 41.4%, p<0.05); and isoniazid preventive therapy (42.3% versus 11.2%, p<0.001). Subjects receiving OST had significantly higher HRQoL than those not receiving it (p<0.001); however, HRQoL did not differ significantly between ICL- and NCL-participants. These findings suggest that OST alone improves quality-of-life, while receiving care in integrated settings collectively and individually improves healthcare quality indicators for PWID. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Changes in the crystalline lens resulting from insertion of a phakic IOL (ICL) into the porcine eye.

PubMed

Fujisawa, Kunitoshi; Shimizu, Kimiya; Uga, Shigekazu; Suzuki, Masanobu; Nagano, Koichi; Murakami, Yuuki; Goseki, Hiroko

2007-01-01

Insertion of a phakic IOL offers these advantages: the corneal optical zone is not dissected or resected; preservation of the crystalline lens results in preservation of the accommodation force; and since the phakic IOL is removable, any error or change in refraction can be countered by exchanging it. However, the cause of secondary cataracts has never been clarified or discussed to date. The following ICL lenses were inserted under general anaesthesia into 20 eyes of ten 3-month-old miniature pigs: a minus lens without holes into five eyes, a plus lens in two eyes, a minus lens with four holes around the lens haptics in three eyes, and a minus lens with a central hole in the optic in three eyes; and seven eyes were used as controls. The anterior segments were then photographed 1 week, 1 month and 3 months after surgery. At 3 months after surgery, Evans blue (EB) was infused into the vitreous under general anaesthesia, and after 30 min, the eyeball was enucleated, fixed and examined. In the case of the ICL without holes, the anterior subcapsular opacities were observed in all the eyes, and the anterior surfaces of the crystalline lenses were not stained with EB. Use of the ICL with four holes around the lens haptics resulted in light staining of the anterior surface of the crystalline lens, but the anterior subcapsular opacities observed were mild. As for the ICL with a hole in the centre of the optic, the anterior surface of the crystalline lens was stained and no anterior subcapsular opacities were observed. The results suggested that the insertion of an ICL brings about a change in the dynamics of the intraocular aqueous humour, reducing its circulation to the anterior surface of the crystalline lens. This is considered to cause a metabolic disturbance of the crystalline lens, resulting in anterior subcapsular opacification.

Integration of Health Services Improves Multiple Healthcare Outcomes Among HIV-infected People Who Inject Drugs in Ukraine

PubMed Central

Bachireddy, Chethan; Soule, Michael C.; Izenberg, Jacob M.; Dvoryak, Sergey; Dumchev, Konstantin; Altice, Frederick L.

2013-01-01

Background People who inject drugs (PWID) experience poor outcomes and fuel HIV epidemics in middle-income countries in Eastern Europe and Central Asia. We assess integrated/co-located (ICL) healthcare for HIV-infected PWID, which despite international recommendations, is neither widely available nor empirically examined. Methods A 2010 cross-sectional study randomly sampled 296 HIV-infected opioid-dependent PWID from two representative HIV-endemic regions in Ukraine where ICL, non-co-located (NCL) and harm reduction/outreach (HRO) settings are available. ICL settings provide onsite HIV, addiction, and tuberculosis services, NCLs only treat addiction, and HROs provide counseling, needles/syringes, and referrals, but no opioid substitution therapy (OST). The primary outcome was receipt of quality healthcare, measured using a quality healthcare indicator (QHI) composite score representing percentage of eight guidelines-based recommended indicators met for HIV, addiction and tuberculosis treatment. The secondary outcomes were individual QHIs and health-related quality-of-life (HRQoL). Results On average, ICL-participants had significantly higher QHI composite scores compared to NCL- and HRO-participants (71.9% versus 54.8% versus 37.0%, p<0.001) even after controlling for potential confounders. Compared to NCL-participants, ICL-participants were significantly more likely to receive antiretroviral therapy (49.5% versus 19.2%, p<0.001), especially if CD4≤200 (93.8% versus 62.5% p<0.05); guideline-recommended OST dosage (57.3% versus 41.4%, p<0.05); and isoniazid preventive therapy (42.3% versus 11.2%, p<0.001). Subjects receiving OST had significantly higher HRQoL than those not receiving it (p<0.001); however, HRQoL did not differ significantly between ICL- and NCL-participants. Conclusions These findings suggest that OST alone improves quality-of-life, while receiving care in integrated settings collectively and individually improves healthcare quality for PWID. PMID:24128379

Vortex depinning as a nonequilibrium phase transition phenomenon: Scaling of current-voltage curves near the low and the high critical-current states in 2 H -Nb S2 single crystals

NASA Astrophysics Data System (ADS)

Bag, Biplab; Sivananda, Dibya J.; Mandal, Pabitra; Banerjee, S. S.; Sood, A. K.; Grover, A. K.

2018-04-01

The vortex depinning phenomenon in single crystals of 2 H -Nb S2 superconductors is used as a prototype for investigating properties of the nonequilibrium (NEQ) depinning phase transition. The 2 H -Nb S2 is a unique system as it exhibits two distinct depinning thresholds, viz., a lower critical current Icl and a higher one Ich. While Icl is related to depinning of a conventional, static (pinned) vortex state, the state with Ich is achieved via a negative differential resistance (NDR) transition where the velocity abruptly drops. Using a generalized finite-temperature scaling ansatz, we study the scaling of current (I)-voltage (V) curves measured across Icl and Ich. Our analysis shows that for I >Icl , the moving vortex state exhibits Arrhenius-like thermally activated flow behavior. This feature persists up to a current value where an inflexion in the IV curves is encountered. While past measurements have often reported similar inflexion, our analysis shows that the inflexion is a signature of a NEQ phase transformation from a thermally activated moving vortex phase to a free flowing phase. Beyond this inflection in IV, a large vortex velocity flow regime is encountered in the 2 H -Nb S2 system, wherein the Bardeen-Stephen flux flow limit is crossed. In this regime the NDR transition is encountered, leading to the high Ich state. The IV curves above Ich we show do not obey the generalized finite-temperature scaling ansatz (as obeyed near Icl). Instead, they scale according to the Fisher's scaling form [Fisher, Phys. Rev. B 31, 1396 (1985), 10.1103/PhysRevB.31.1396] where we show thermal fluctuations do not affect the vortex flow, unlike that found for depinning near Icl.

Anomalous Aortic Origin of Coronary Arteries in the Young: Echocardiographic Evaluation With Surgical Correlation.

PubMed

Lorber, Richard; Srivastava, Shubhika; Wilder, Travis J; McIntyre, Susan; DeCampli, William M; Williams, William G; Frommelt, Peter C; Parness, Ira A; Blackstone, Eugene H; Jacobs, Marshall L; Mertens, Luc; Brothers, Julie A; Herlong, J René

2015-11-01

This study sought to compare findings from institutional echocardiographic reports with imaging core laboratory (ICL) review of corresponding echocardiographic images and operative reports in 159 patients with anomalous aortic origin of a coronary artery (AAOCA). The study also sought to develop a "best practice" protocol for imaging and interpreting images in establishing the diagnosis of AAOCA. AAOCA is associated with sudden death in the young. Underlying anatomic risk factors that can cause ischemia-related events include coronary arterial ostial stenosis, intramural course of the proximal coronary within the aortic wall, interarterial course, and potential compression between the great arteries. Consistent protocols for diagnosing and evaluating these features are lacking, potentially precluding the ability to risk stratify patients based on evidence and plan surgical strategy. For a prescribed set of anatomic AAOCA features, percentages of missing data in institutional echocardiographic reports were calculated. For each feature, agreement among institutional echocardiographic reports, ICL review of images, and surgical reports was evaluated using the weighted kappa statistic. An echocardiographic imaging protocol was developed heuristically to reduce differences between institutional reports and ICL review. A total of 13%, 33%, and 62% of echocardiograms were missing images enabling diagnosis of intra-arterial course, proximal intramural course, and high ostial takeoff, respectively. There was poor agreement between institutional reports and ICL review for diagnosis of origin of coronary artery, interarterial course, intramural course, and acute angle takeoff (kappa = 0.74, 0.11, -0.03, 0.13, respectively). Surgical findings were also significantly different from those of reports, and to a lesser extent ICL reviews. The resulting protocol contains technical recommendations for imaging each of these features. Poor agreement between institutional reports and ICL review for AAOCA suggests need for an imaging protocol to permit evidence-based risk stratification and surgical planning. Even then, delineation of echocardiographic details in AAOCA will remain imperfect. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Improvements in Intracorporeal Lithotripters for Percutaneous Nephrolithotomy

NASA Astrophysics Data System (ADS)

Kuo, Ramsay L.

2007-04-01

Percutaneous nephrolithotomy (PNL) is an effective minimally invasive surgical approach for the treatment of large renal stone burden. Intracorporeal lithotripters (ICL) are utilized during PNL to fragment calculi, with some devices capable of concurrently removing fragments as well. Much progress has been made in the design of ICL devices, resulting in potentially more efficient treatment of nephrolithiasis.

Active tuberculosis patients have high levels of IgA anti-alpha-crystallin and isocitrate lyase proteins.

PubMed

Talavera-Paulín, M; García-Morales, L; Ruíz-Sánchez, B P; Caamal-Ley, Á D; Hernández-Solis, A; Ramírez-Casanova, E; Cicero-Sabido, R; Espitia, C; Helguera-Repetto, C; González-Y-Merchand, J A; Flores-Mejía, R; Estrada-Parra, S; Estrada-García, I; Chacón-Salinas, R; Wong-Baeza, I; Serafín-López, J

2016-12-01

Mexico City, Mexico. To identify proteins synthetised by Mycobacterium tuberculosis in hypoxic culture, which resemble more closely a granuloma environment than aerobic culture, and to determine if they are recognised by antibodies from patients with active pulmonary tuberculosis (PTB). Soluble extracts from M. tuberculosis H37Rv cultured under aerobic or hypoxic conditions were analysed using two-dimensional polyacrylamide gel electrophoresis, and proteins over-expressed under hypoxia were identified by mass spectrometry. The presence of immunoglobulin (Ig) G, IgA and IgM antibodies against these proteins was determined in the serum of 42 patients with active PTB and 42 healthy controls. We selected three M. tuberculosis H37Rv proteins (alpha-crystallin protein [Acr, Rv2031c], universal stress protein Rv2623 and isocitrate lyase [ICL, RV0467]) that were over-expressed under hypoxia. Titres of anti-Acr and anti-ICL IgA antibodies were higher in patients than in healthy controls, with an area under the receiver operating characteristic curve of 0.71 for anti-ICL IgA antibodies. ICL could be used in combination with other M. tuberculosis antigens to improve the sensitivity and specificity of current serological TB diagnostic methods.

The COX-2 Selective Blocker Etodolac Inhibits TNFα-Induced Apoptosis in Isolated Rabbit Articular Chondrocytes

PubMed Central

Kumagai, Kousuke; Kubo, Mitsuhiko; Imai, Shinji; Toyoda, Futoshi; Maeda, Tsutomu; Okumura, Noriaki; Matsuura, Hiroshi; Matsusue, Yoshitaka

2013-01-01

Chondrocyte apoptosis contributes to the disruption of cartilage integrity in osteoarthritis (OA). Recently, we reported that activation of volume-sensitive Cl− current (ICl,vol) mediates cell shrinkage, triggering apoptosis in rabbit articular chondrocytes. A cyclooxygenase (COX) blocker is frequently used for the treatment of OA. In the present study, we examined in vitro effects of selective blockers of COX on the TNFα-induced activation of ICl,vol in rabbit chondrocytes using the patch-clamp technique. Exposure of isolated chondrocytes to TNFα resulted in an obvious increase in membrane Cl− conductance. The TNFα-evoked Cl− current exhibited electrophysiological and pharmacological properties similar to those of ICl,vol. Pretreatment of cells with selective COX-2 blocker etodolac markedly inhibited ICl,vol activation by TNFα as well as subsequent apoptotic events such as apoptotic cell volume decrease (AVD) and elevation of caspase-3/7 activity. In contrast, a COX-1 blocker had no effect on the decrease in cell volume or the increase in caspase-3/7 activity induced by TNFα. Thus, the COX-2-selective blocker had an inhibitory effect on TNFα-induced apoptotic events, which suggests that this drug would have efficacy for the treatment of OA. PMID:24084720

Photostop of iodine atoms from electrically oriented ICl molecules

NASA Astrophysics Data System (ADS)

Bao, Da-Xiao; Deng, Lian-Zhong; Xu, Liang; Yin, Jian-Ping

2015-11-01

The dynamics of photostopping iodine atoms from electrically oriented ICl molecules was numerically studied based on their orientational probability distribution functions. Velocity distributions of the iodine atoms and their production rates were investigated for orienting electrical fields of various intensities. For the ICl precursor beams with an initial rotational temperature of ∼ 1 K, the production of the iodine atoms near zero speed will be improved by about ∼ 5 times when an orienting electrical field of ∼ 200 kV/cm is present. A production rate of ∼ 0.5‰ is obtained for photostopped iodine atoms with speeds less than 10 m/s, which are suitable for magnetic trapping. The electrical orientation of ICl precursors and magnetic trapping of photostopped iodine atoms in situ can be conveniently realized with a pair of charged ring magnets. With the maximal value of the trapping field being ∼ 0.28 T, the largest trapping speed is ∼ 7.0 m/s for the iodine atom. Project supported by the National Natural Science Foundation of China (Grant Nos. 11034002, 61205198, and 11274114) and the National Key Basic Research and Development Program of China (Grant No. 2011CB921602).

The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion.

PubMed

Khunweeraphong, Narakorn; Stockner, Thomas; Kuchler, Karl

2017-10-23

The human ABC transporter ABCG2 (Breast Cancer Resistance Protein, BCRP) is implicated in anticancer resistance, in detoxification across barriers and linked to gout. Here, we generate a novel atomic model of ABCG2 using the crystal structure of ABCG5/G8. Extensive mutagenesis verifies the structure, disclosing hitherto unrecognized essential residues and domains in the homodimeric ABCG2 transporter. The elbow helix, the first intracellular loop (ICL1) and the nucleotide-binding domain (NBD) constitute pivotal elements of the architecture building the transmission interface that borders a central cavity which acts as a drug trap. The transmission interface is stabilized by salt-bridge interactions between the elbow helix and ICL1, as well as within ICL1, which is essential to control the conformational switch of ABCG2 to the outward-open drug-releasing conformation. Importantly, we propose that ICL1 operates like a molecular spring that holds the NBD dimer close to the membrane, thereby enabling efficient coupling of ATP hydrolysis during the catalytic cycle. These novel mechanistic data open new opportunities to therapeutically target ABCG2 in the context of related diseases.

Assessment of the information content of patterns: an algorithm

NASA Astrophysics Data System (ADS)

Daemi, M. Farhang; Beurle, R. L.

1991-12-01

A preliminary investigation confirmed the possibility of assessing the translational and rotational information content of simple artificial images. The calculation is tedious, and for more realistic patterns it is essential to implement the method on a computer. This paper describes an algorithm developed for this purpose which confirms the results of the preliminary investigation. Use of the algorithm facilitates much more comprehensive analysis of the combined effect of continuous rotation and fine translation, and paves the way for analysis of more realistic patterns. Owing to the volume of calculation involved in these algorithms, extensive computing facilities were necessary. The major part of the work was carried out using an ICL 3900 series mainframe computer as well as other powerful workstations such as a RISC architecture MIPS machine.

Survey of new vector computers: The CRAY 1S from CRAY research; the CYBER 205 from CDC and the parallel computer from ICL - architecture and programming

NASA Technical Reports Server (NTRS)

Gentzsch, W.

1982-01-01

Problems which can arise with vector and parallel computers are discussed in a user oriented context. Emphasis is placed on the algorithms used and the programming techniques adopted. Three recently developed supercomputers are examined and typical application examples are given in CRAY FORTRAN, CYBER 205 FORTRAN and DAP (distributed array processor) FORTRAN. The systems performance is compared. The addition of parts of two N x N arrays is considered. The influence of the architecture on the algorithms and programming language is demonstrated. Numerical analysis of magnetohydrodynamic differential equations by an explicit difference method is illustrated, showing very good results for all three systems. The prognosis for supercomputer development is assessed.

Dependence of the electronic absorption spectra of aqueous solutions of iodine monochloride on the conditions of dilution and storage time

NASA Astrophysics Data System (ADS)

Klyubin, V. V.; Klyubina, K. A.; Makovetskaya, K. N.

2017-04-01

The electronic absorption spectra of aqueous solutions of iodine monochloride ICl are studied. The spectra of as-prepared solutions display the absorption band associated with hydrated ICl molecules. An additional band indicating that molecular iodine was formed in the solution emerges in the spectrum as dissolution takes place. Only the band belonging to iodine monochloride remains in the absorption spectra, and no additional bands appear after chloride anions Cl- are added to the solution. The absorption spectrum becomes more complex when ICl is dissolved in an alkaline medium. The band belonging to molecular iodine emerges in the spectra at low alkali concentrations, while being transformed to other shorter-wavelength bands at high alkali concentrations (pH ≥ 12).

The interhalogens IF and ICI as visible oscillators or amplifiers

NASA Technical Reports Server (NTRS)

Eden, J. G.; Dlabal, M. L.; Hutchison, S. B.

1981-01-01

The kinetic and spectroscopic properties of the interhalogens are reviewed, with emphasis on the iodine-monochloride (ICl) and iodine-monofluoride (IF) systems; the latter having produced 140 kW, 30 nsec FWHM pulses at 491 and 485 nm and may be scaled to the tens of millijoules per pulse level. Gain in excess of 1.0%/cm was observed across the entire IF blue-green band, demonstrating potentially wide tunability. Although ICl has not yet lased, its peak small-signal gain of 1.3%/cm and negligible background absorption in discharge plasmas make it an attractive candidate for a violet amplifier. The formation kinetics of IF- and ICl-excimer lasers in electron beam or discharge-produced plasmas, and the potential and limitations of these molecules as visible lasers or amplifiers are also discussed.

Comparison of optical quality after implantable collamer lens implantation and wavefront-guided laser in situ keratomileusis

PubMed Central

Liu, Hong-Ting; Zhou, Zhou; Luo, Wu-Qiang; He, Wen-Jing; Agbedia, Owhofasa; Wang, Jiang-Xia; Huang, Jian-Zhong; Gao, Xin; Kong, Min; Li, Min; Li, Li

2018-01-01

AIM To compare the optical quality after implantation of implantable collamer lens (ICL) and wavefront-guided laser in situ keratomileusis (WG-LASIK). METHODS The study included 40 eyes of 22 patients with myopia who accepted ICL implantation and 40 eyes of 20 patients with myopia who received WG-LASIK. Before surgery and three months after surgery, the objective scattering index (OSI), the values of modulation transfer function (MTF) cutoff frequency, Strehl ratio, and the Optical Quality Analysis System (OQAS) values (OVs) were accessed. The higher order aberrations (HOAs) data including coma, trefoil, spherical, 2nd astigmatism and tetrafoil were also obtained. For patients with pupil size <6 mm, HOAs data were analyzed for 4 mm-pupil diameter. For patients with pupil size ≥6 mm, HOAs data were calculated for 6 mm-pupil diameter. Visual acuity, refraction, pupil size and intraocular pressures were also recorded. RESULTS In both ICL and WG-LASIK group, significant improvements in visual acuities were found postoperatively, with a significant reduction in spherical equivalent (P< 0.001). After the ICL implantation, the OSI decreased slightly from 2.34±1.92 to 2.24±1.18 with no statistical significance (P=0.62). While in WG-LASIK group, the OSI significantly increased from 0.68±0.43 preoperatively to 0.91±0.53 postoperatively (Wilcoxon signed ranks test, P=0.000). None of the mean MTF cutoff frequency, Strehl ratio, OVs showed statistically significant changes in both ICL and WG-LASIK groups. In the ICL group, there were no statistical differences in the total HOAs for either 4 mm-pupil or 6 mm-pupil. In the WG-LASIK group, the HOA parameters increased significantly at 4 mm-pupil. The total ocular HOAs, coma, spherical and 2nd astigmatism were 0.12±0.06, 0.06±0.03, 0.00±0.03, 0.02±0.01, respectively. After the operation, these values were increased into 0.16±0.07, 0.08±0.05, -0.04±0.04, 0.03±0.01 respectively (Wilcoxon signed ranks test, all P<0.05). At 6 mm-pupil, the induction of total HOAs was not statistically significant in the WG-LASIK group. CONCLUSION ICL implantation has a less disturbance to optical quality than WG-LASIK. The OQAS is a valuable complementary measurement to the wavefront aberrometers in evaluating the optical quality. PMID:29675387

Comparison of optical quality after implantable collamer lens implantation and wavefront-guided laser in situ keratomileusis.

PubMed

Liu, Hong-Ting; Zhou, Zhou; Luo, Wu-Qiang; He, Wen-Jing; Agbedia, Owhofasa; Wang, Jiang-Xia; Huang, Jian-Zhong; Gao, Xin; Kong, Min; Li, Min; Li, Li

2018-01-01

To compare the optical quality after implantation of implantable collamer lens (ICL) and wavefront-guided laser in situ keratomileusis (WG-LASIK). The study included 40 eyes of 22 patients with myopia who accepted ICL implantation and 40 eyes of 20 patients with myopia who received WG-LASIK. Before surgery and three months after surgery, the objective scattering index (OSI), the values of modulation transfer function (MTF) cutoff frequency, Strehl ratio, and the Optical Quality Analysis System (OQAS) values (OVs) were accessed. The higher order aberrations (HOAs) data including coma, trefoil, spherical, 2 nd astigmatism and tetrafoil were also obtained. For patients with pupil size <6 mm, HOAs data were analyzed for 4 mm-pupil diameter. For patients with pupil size ≥6 mm, HOAs data were calculated for 6 mm-pupil diameter. Visual acuity, refraction, pupil size and intraocular pressures were also recorded. In both ICL and WG-LASIK group, significant improvements in visual acuities were found postoperatively, with a significant reduction in spherical equivalent ( P < 0.001). After the ICL implantation, the OSI decreased slightly from 2.34±1.92 to 2.24±1.18 with no statistical significance ( P =0.62). While in WG-LASIK group, the OSI significantly increased from 0.68±0.43 preoperatively to 0.91±0.53 postoperatively (Wilcoxon signed ranks test, P =0.000). None of the mean MTF cutoff frequency, Strehl ratio, OVs showed statistically significant changes in both ICL and WG-LASIK groups. In the ICL group, there were no statistical differences in the total HOAs for either 4 mm-pupil or 6 mm-pupil. In the WG-LASIK group, the HOA parameters increased significantly at 4 mm-pupil. The total ocular HOAs, coma, spherical and 2 nd astigmatism were 0.12±0.06, 0.06±0.03, 0.00±0.03, 0.02±0.01, respectively. After the operation, these values were increased into 0.16±0.07, 0.08±0.05, -0.04±0.04, 0.03±0.01 respectively (Wilcoxon signed ranks test, all P <0.05). At 6 mm-pupil, the induction of total HOAs was not statistically significant in the WG-LASIK group. ICL implantation has a less disturbance to optical quality than WG-LASIK. The OQAS is a valuable complementary measurement to the wavefront aberrometers in evaluating the optical quality.

Protein crystal growth in low gravity

NASA Technical Reports Server (NTRS)

Feigelson, Robert S.

1992-01-01

A study is presented of the crystallization of isocitrate lyase (ICL) and the influence of the lack of thermal solutal convection in microgravity on the morphology of ICL crystals is discussed. The latest results of studies with thermonucleation are presented. These include the nucleation of a protein with retrograde solubility and an unknown solubility curve. A new design for a more microgravity compatible thermonuclear is presented.

Structure-based screening and molecular dynamics simulations offer novel natural compounds as potential inhibitors of Mycobacterium tuberculosis isocitrate lyase.

PubMed

Shukla, Rohit; Shukla, Harish; Sonkar, Amit; Pandey, Tripti; Tripathi, Timir

2018-06-01

Mycobacterium tuberculosis is the etiological agent of tuberculosis in humans and is responsible for more than two million deaths annually. M. tuberculosis isocitrate lyase (MtbICL) catalyzes the first step in the glyoxylate cycle, plays a pivotal role in the persistence of M. tuberculosis, which acts as a potential target for an anti-tubercular drug. To identify the potential anti-tuberculosis compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,748) against the MtbICL structure. The ligands were docked against MtbICL in three sequential docking modes that resulted in 340 ligands having better docking score. These compounds were evaluated for Lipinski and ADMET prediction, and 27 compounds were found to fit well with re-docking studies. After refinement by molecular docking and drug-likeness analyses, three potential inhibitors (ZINC1306071, ZINC2111081, and ZINC2134917) were identified. These three ligands and the reference compounds were further subjected to molecular dynamics simulation and binding energy analyses to compare the dynamic structure of protein after ligand binding and the stability of the MtbICL and bound complexes. The binding free energy analyses were calculated to validate and capture the intermolecular interactions. The results suggested that the three compounds had a negative binding energy with -96.462, -143.549, and -122.526 kJ mol -1 for compounds with IDs ZINC1306071, ZINC2111081, and ZINC2134917, respectively. These lead compounds displayed substantial pharmacological and structural properties to be drug candidates. We concluded that ZINC2111081 has a great potential to inhibit MtbICL and would add to the drug discovery process against tuberculosis.

Assessment of subjective intraocular forward scattering and quality of vision after posterior chamber phakic intraocular lens with a central hole (Hole ICL) implantation.

PubMed

Iijima, Ayaka; Shimizu, Kimiya; Yamagishi, Mayumi; Kobashi, Hidenaga; Igarashi, Akihito; Kamiya, Kazutaka

2016-12-01

To evaluate the subjective intraocular forward scattering and quality of vision after posterior chamber phakic intraocular lens with a central hole (Hole ICL, STAAR Surgical) implantation. We prospectively examined 29 eyes of 29 consecutive patients (15 men and 14 women; ages, 37.2 ± 8.8 years) undergoing Hole ICL implantation. We assessed the values of the logarithmic straylight value [log (s)] using a straylight meter (C-Quant ™ , Oculus) preoperatively and 3 months postoperatively. The patients completed a questionnaire detailing symptoms on a quantitative grading scale (National Eye Institute Refractive Error Quality of Life Instrument-42; NEI RQL-42) 3 months postoperatively. We compared the preoperative and postoperative values of the log(s) and evaluated the correlation of these values with patient subjective symptoms. The mean log(s) was not significantly changed, from 1.07 ± 0.20 preoperatively, to 1.06 ± 0.17 postoperatively (Wilcoxon signed-rank test, p = 0.641). There was a significant correlation between the preoperative and postoperative log(s) (Spearman's correlation coefficient r = 0.695, p < 0.001). The postoperative log(s) was significantly associated with the scores of glare in the questionnaire (Spearman's correlation coefficient r = -0.575, p = 0.017). According to our experience, Hole ICL implantation does not induce a significant additional change in the subjective intraocular forward scattering. The symptom of glare after Hole ICL implantation was significantly correlated with the postoperative intraocular forward scattering in relation to the preoperative one. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Constrained dynamics of the sole tryptophan in the third intracellular loop of the serotonin1A receptor.

PubMed

Pal, Sreetama; Aute, Ramdas; Sarkar, Parijat; Bose, Shroddha; Deshmukh, Mandar V; Chattopadhyay, Amitabha

2018-06-01

G protein-coupled receptors (GPCRs) are major signaling proteins in eukaryotic cells and are important drug targets. In spite of their role in GPCR function, the extramembranous regions of GPCRs are relatively less appreciated. The third intracellular loop (ICL3), which connects transmembrane helices V and VI, is important in this context since its crucial role in signaling has been documented for a number of GPCRs. Unfortunately, the structure of this loop is generally not visualized in x-ray crystallographic studies since this flexible loop is either stabilized using a monoclonal antibody or replaced with lysozyme. In this work, we expressed and purified the ICL3 region of the serotonin 1A receptor and monitored its motional restriction and organization utilizing red edge excitation shift (REES) of its sole tryptophan and circular dichroism (CD) spectroscopy. Our results show that the tryptophan in ICL3 exhibits REES of 4 nm, implying that it is localized in a restricted microenvironment. These results are further supported by wavelength-selective changes in fluorescence anisotropy and lifetime. This constrained dynamics was relaxed upon denaturation of the peptide, thereby suggesting the involvement of the peptide secondary structure in the observed motional restriction, as evident from CD spectroscopy and apparent rotational correlation time. To the best of our knowledge, these results constitute one of the first measurements of motional constraint in the ICL3 region of GPCRs. Our results are relevant in the context of the reported intrinsically disordered nature of ICL3 and its role in providing functional diversity to GPCRs due to conformational plasticity. Copyright © 2018 Elsevier B.V. All rights reserved.

Correlation of Thermal Stability and Structural Distortion of DNA Interstrand Cross-Links Produced from Oxidized Abasic Sites with Their Selective Formation and Repair.

PubMed

Ghosh, Souradyuti; Greenberg, Marc M

2015-10-13

C4'-oxidized (C4-AP) and C5'-oxidized abasic sites (DOB) that are produced following abstraction of a hydrogen atom from the DNA backbone reversibly form cross-links selectively with dA opposite a 3'-adjacent nucleotide, despite the comparable proximity of an opposing dA. A previous report on UvrABC incision of DNA substrates containing stabilized analogues of the ICLs derived from C4-AP and DOB also indicated that the latter is repaired more readily by nucleotide excision repair [Ghosh, S., and Greenberg, M. M. (2014) Biochemistry 53, 5958-5965]. The source for selective cross-link formation was probed by comparing the reactivity of ICL analogues of C4-AP and DOB that mimic the preferred and disfavored cross-links with that of reagents that indirectly detect distortion by reacting with the nucleobases. The disfavored C4-AP and DOB analogues were each more reactive than the corresponding preferred cross-link substrates, suggesting that the latter are more stable, which is consistent with selective ICL formation. In addition, the preferred DOB analogue is more reactive than the respective C4-AP ICL, which is consistent with its more efficient incision by UvrABC. The conclusions drawn from the chemical probing experiments are corroborated by UV melting studies. The preferred ICLs exhibit melting temperatures higher than those of the corresponding disfavored isomers. These studies suggest that oxidized abasic sites form reversible interstrand cross-links with dA opposite the 3'-adjacent thymidine because these products are more stable and the thermodynamic preference is reflected in the transition states for their formation.

Central endoscopy reads in inflammatory bowel disease clinical trials: The role of the imaging core lab

PubMed Central

Ahmad, Harris; Berzin, Tyler M.; Yu, Hui Jing; Huang, Christopher S.; Mishkin, Daniel S.

2014-01-01

Clinical trials in inflammatory bowel disease (IBD) are evolving at a rapid pace by employing central reading for endoscopic mucosal assessment in a field that was, historically, largely based on assessments by local physicians. This transition from local to central reading carries with it numerous technical, operational, and scientific challenges, many of which can be resolved by imaging core laboratories (ICLs), a concept that has a longer history in clinical trials in a number of diseases outside the realm of gastroenterology. For IBD trials, ICLs have the dual goals of providing objective, consistent assessments of endoscopic findings using central-reading paradigms whilst providing important expertise with regard to operational issues and regulatory expectations. This review focuses on current approaches to using ICLs for central endoscopic reading in IBD trials. PMID:24994835

Occurrence of a number of enzymes involved in either gluconeogenesis or other processes in the pericarp of three cultivars of grape (Vitis vinifera L.) during development.

PubMed

Famiani, Franco; Moscatello, Stefano; Ferradini, Nicoletta; Gardi, Tiziano; Battistelli, Alberto; Walker, Robert P

2014-11-01

It is uncertain whether the enzymes pyruvate orthophosphate dikinase (PPDK) or isocitrate lyase (ICL) are present in the pericarp of grape, in which they could function in gluconeogenesis. The occurrence of these and other enzymes was investigated in the pericarp of three cultivars of grape (Vitis vinifera L.). In particular, the abundance of the enzymes aldolase, glutamine synthase (GS), acid invertase, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), phosphoenolpyruvate carboxylase (PEPC), PPDK and ICL were determined during the development of the pericarp of the cultivars Cabernet Sauvignon, Chardonnay and Zibibbo. PPDK and ICL were not detected at any stage of development. Each of the other enzymes showed different changes in abundance during development. However, for a given enzyme its changes in abundance were similar in each cultivar. In the ripe pericarp of Cabernet Sauvignon, PEPC, cytosolic GS and aldolase were equally distributed between the vasculature and parenchyma cells of the flesh and skin. The absence or very low abundance of PPDK provides strong evidence that any gluconeogenesis from malate utilises phosphoenolpyruvate carboxykinase (PEPCK). The absence or very low abundance of ICL in the pericarp precludes any gluconeogenesis from ethanol. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The FANCJ/MutLα interaction is required for correction of the cross-link response in FA-J cells

PubMed Central

Peng, Min; Litman, Rachel; Xie, Jenny; Sharma, Sudha; Brosh, Robert M; Cantor, Sharon B

2007-01-01

FANCJ also called BACH1/BRIP1 was first linked to hereditary breast cancer through its direct interaction with BRCA1. FANCJ was also recently identified as a Fanconi anemia (FA) gene product, establishing FANCJ as an essential tumor suppressor. Similar to other FA cells, FANCJ-null (FA-J) cells accumulate 4N DNA content in response to DNA interstrand crosslinks (ICLs). This accumulation is corrected by reintroduction of wild-type FANCJ. Here, we show that FANCJ interacts with the mismatch repair complex MutLα, composed of PMS2 and MLH1. Specifically, FANCJ directly interacts with MLH1 independent of BRCA1, through its helicase domain. Genetic studies reveal that FANCJ helicase activity and MLH1 binding, but not BRCA1 binding, are essential to correct the FA-J cells' ICL-induced 4N DNA accumulation and sensitivity to ICLs. These results suggest that the FANCJ/MutLα interaction, but not FANCJ/BRCA1 interaction, is essential for establishment of a normal ICL-induced response. The functional role of the FANCJ/MutLα complex demonstrates a novel link between FA and MMR, and predicts a broader role for FANCJ in DNA damage signaling independent of BRCA1. PMID:17581638

Preoperative Biometric Parameters Predict the Vault after ICL Implantation: A Retrospective Clinical Study.

PubMed

Zheng, Qian-Yin; Xu, Wen; Liang, Guan-Lu; Wu, Jing; Shi, Jun-Ting

2016-01-01

To investigate the correlation between the preoperative biometric parameters of the anterior segment and the vault after implantable Collamer lens (ICL) implantation via this retrospective study. Retrospective clinical study. A total of 78 eyes from 41 patients who underwent ICL implantation surgery were included in this study. Preoperative biometric parameters, including white-to-white (WTW) diameter, central corneal thickness, keratometer, pupil diameter, anterior chamber depth, sulcus-to-sulcus diameter, anterior chamber area (ACA) and central curvature radius of the anterior surface of the lens (Lenscur), were measured. Lenscur and ACA were measured with Rhinoceros 5.0 software on the image scanned with ultrasound biomicroscopy (UBM). The vault was assessed by UBM 3 months after surgery. Multiple stepwise regression analysis was employed to identify the variables that were correlated with the vault. The results showed that the vault was correlated with 3 variables: ACA (22.4 ± 4.25 mm2), WTW (11.36 ± 0.29 mm) and Lenscur (9.15 ± 1.21 mm). The regressive equation was: vault (mm) = 1.785 + 0.017 × ACA + 0.051 × Lenscur - 0.203 × WTW. Biometric parameters of the anterior segment (ACA, WTW and Lenscur) can predict the vault after ICL implantation using a new regression equation. © 2016 The Author(s) Published by S. Karger AG, Basel.

Multi-species sensing using multi-mode absorption spectroscopy with mid-infrared interband cascade lasers

NASA Astrophysics Data System (ADS)

O'Hagan, S.; Northern, J. H.; Gras, B.; Ewart, P.; Kim, C. S.; Kim, M.; Merritt, C. D.; Bewley, W. W.; Canedy, C. L.; Vurgaftman, I.; Meyer, J. R.

2016-06-01

The application of an interband cascade laser, ICL, to multi-mode absorption spectroscopy, MUMAS, in the mid-infrared region is reported. Measurements of individual mode linewidths of the ICL, derived from the pressure dependence of lineshapes in MUMAS signatures of single, isolated, lines in the spectrum of HCl, were found to be in the range 10-80 MHz. Multi-line spectra of methane were recorded using spectrally limited bandwidths, of approximate width 27 cm-1, defined by an interference filter, and consist of approximately 80 modes at spectral locations spanning the 100 cm-1 bandwidth of the ICL output. Calibration of the methane pressures derived from MUMAS data using a capacitance manometer provided measurements with an uncertainty of 1.1 %. Multi-species sensing is demonstrated by the simultaneous detection of methane, acetylene and formaldehyde in a gas mixture. Individual partial pressures of the three gases are derived from best fits of model MUMAS signatures to the data with an experimental error of 10 %. Using an ICL, with an inter-mode interval of ~10 GHz, MUMAS spectra were recorded at pressures in the range 1-10 mbar, and, based on the data, a potential minimum detection limit of the order of 100 ppmv is estimated for MUMAS at atmospheric pressure using an inter-mode interval of 80 GHz.

Molecular Mechanisms Underlying Genomic Instability in Brca-Deficient Cells

DTIC Science & Technology

2012-03-01

Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2...repair pathway comprising at least 15 gene products. Mutation of any of these genes causes the human disease Fanconi anemia (FA), which is associated...genetic deficiency in components of the Fanconi anemia (FA) pathway (Wang, 2007). Cells from FA patients, or knockout mice with deficiencies in the FA

Central endoscopy reads in inflammatory bowel disease clinical trials: The role of the imaging core lab.

PubMed

Ahmad, Harris; Berzin, Tyler M; Yu, Hui Jing; Huang, Christopher S; Mishkin, Daniel S

2014-08-01

Clinical trials in inflammatory bowel disease (IBD) are evolving at a rapid pace by employing central reading for endoscopic mucosal assessment in a field that was, historically, largely based on assessments by local physicians. This transition from local to central reading carries with it numerous technical, operational, and scientific challenges, many of which can be resolved by imaging core laboratories (ICLs), a concept that has a longer history in clinical trials in a number of diseases outside the realm of gastroenterology. For IBD trials, ICLs have the dual goals of providing objective, consistent assessments of endoscopic findings using central-reading paradigms whilst providing important expertise with regard to operational issues and regulatory expectations. This review focuses on current approaches to using ICLs for central endoscopic reading in IBD trials. © The Author(s) 2014. Published by Oxford University Press and the Digestive Science Publishing Co. Limited.

Transient anterior subcapsular vacuolar change of the crystalline lens in patients after posterior chamber phakic intraocular lens implantation.

PubMed

Chung, Jin Kwon; Shin, Jin Hee; Lee, Sung Jin

2013-10-25

We present two cases of transient vacuolar changes in the anterior subcapsular space of the crystalline lens in patients after posterior chamber phakic intraocular lens implantation. Implantable collamer lenses (ICL) were implanted in healthy myopic patients. Vacuolar changes developed just after the irrigating procedure through the narrow space between the ICL and the crystalline lens. Slit-lamp examinations and spectral domain optical coherence tomography showed bleb-like lesions in the anterior subcapsular space of one eye in each case, though the lesions gradually improved without visual deterioration. Consequently, the lesions turned into a few anterior subcapsular small faint opacities. Direct irrigation of the narrow space confined by the ICL and the crystalline lens is at risk for the development of vacuolar changes in the crystalline lens. The observed spontaneous reversal indicates that surgeons should not rush to surgical intervention but rather opt for close follow over several weeks.

FancJ regulates interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1

PubMed Central

Zou, Jianqiu; Tian, Fen; Li, Ji; Pickner, Wyatt; Long, Molly; Rezvani, Khosrow; Wang, Hongmin; Zhang, Dong

2013-01-01

Summary DNA damage response (DDR) and the centrosome cycle are two of the most critical processes for maintaining a stable genome in animals. Sporadic evidence suggests a connection between these two processes. Here, we report our findings that six Fanconi Anemia (FA) proteins, including FancI and FancJ, localize to the centrosome. Intriguingly, we found that the localization of FancJ to the mother centrosome is stimulated by a DNA interstrand crosslinker, Mitomycin C (MMC). We further show that, in addition to its role in interstrand crosslinking (ICL) repair, FancJ also regulates the normal centrosome cycle as well as ICL induced centrosome amplification by activating the polo-like kinase 1 (PLK1). We have uncovered a novel function of FancJ in centrosome biogenesis and established centrosome amplification as an integral part of the ICL response. PMID:24167712

Interferon induction by two 2'-modified double-helical RNAs, poly(2'-fluoro-2'-deoxyinosinic acid) x poly(cytidylic acid) and poly(2'-chloro-2'-deoxyinosinic acid) x poly(cytidylic acid).

PubMed

De Clercq, E; Stollar, B D; Hobbs, J; Fukui, T; Kakiuchi, N; Ikehara, M

1980-01-01

In addition to the 2'-azido analogue of (I)n x (C)n, (dIn3)n x (C)n, we have found two other (I)n x (C)n analogues, (dIfl)n x (C)n and (dIcl)n x (C)n, in which the 2'-hydroxyls of the (I)n strand are replaced by either fluorine or chlorine, to be highly effective in inducing interferon. This contrasted with the lack of interferon-inducing activity noted for various other 2'-halogeno analogues of (I)n x (C)n and (A)n x (U)n, i.e. (I)n x (dCcl)n, (dAfl)n x (U)n, (dAcl)n x (U)n, (A)n x (dUfl)n and (A)n x (dUcl)n. In most assay systems, viz. primary rabbit kidney cells, human diploid fibroblasts, HeLa cells, interferon-primed mouse L-929 cells, and intact rabbits, (dIfl)n x (C)n and (dIcl)n x (C)n induced interferon levels that were comparable to those induced by (I)n x (C)n. There was one particular system (L-929 cells treated with DEAE-dextran), however, in which (dIfl)n x (C)n and (dIcl)n x (C)n, unlike (I)n x (C)n, failed to stimulate interferon production. As monitored by both radiochemical and biological means, (dIfl)n x (C)n and, to a lesser extent, (dIcl)n x (C)n were more resistant to degradation by ribonuclease A, T1 and human serum nucleases than was (I)n x (C)n. In their reactivity towards antibodies to double-stranded RNA (dIfl)n x (C)n and (dIcl)n x (C)n conformed more closely to (I)n x (C)n than did other 2'-substituted (e.g. 2'-O-methyl or 2'-O-ethyl) analogues of (I)n x (C)n. The high interferon-inducing potency of (dIfl)n x (C)n and (dIcl)n x (C)n has both theoretical and practical implications. While our findings suggest that (dIfl)n x (C)n and (dIcl)n x (C)n should be further explored for their therapeutic potentials, they also strengthen the notion that the interferon-inducing capacity, and possibly other biological functions of double-stranded RNAs is dependent on the recognition of the overall conformation of the polynucleotide rather than on the binding of specific functional groups such as the 2'-hydroxyl group.

Outcome after treatment of ametropia with implantable contact lenses.

PubMed

Lackner, Birgit; Pieh, Stefan; Schmidinger, Gerald; Hanselmayer, Georg; Dejaco-Ruhswurm, Irene; Funovics, Martin A; Skorpik, Christian

2003-11-01

To evaluate long-term results after insertion of implantable contact lenses (ICLs) in phakic eyes. Prospective, noncomparative, interventional case series. Seventy-five phakic eyes (65 myopic, 10 hyperopic eyes) of 45 patients aged 21.7 to 60.6 years were included. STAAR Collamer Implantable Contact Lenses (STAAR Surgical Inc., Nidau, Switzerland) were implanted for correction of high myopia and hyperopia. Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were determined. Presence of lens opacification and the distance between the ICL and the crystalline lens were assessed by slit-lamp examination before surgery and at 1, 3, 6 months, and yearly after lens implantation. Preoperative mean spherical equivalent was -16.23+/-5.29 diopters (D) for myopic eyes and +7.88 +/-1.46 D for hyperopic eyes. After ICL implantation, mean residual refractive error was -1.77+/-2.17 D in myopic patients and +0.44+/-0.69 D in hyperopic patients. Preoperative mean UCVA was Snellen 0.03+/-0.03 for myopic patients and Snellen 0.12+/-0.16 for hyperopic patients. Preoperative mean BCVA was Snellen 0.49+/-0.23 for myopic patients and Snellen 0.82+/-0.23 for hyperopic patients. After ICL implantation, mean UCVA up to the end of individual observation time was Snellen 0.36+/-0.36 for myopic patients and Snellen 0.58+/-0.28 for hyperopic patients. Mean BCVA was Snellen 0.73+/-0.26 for myopic and Snellen 0.80+/-0.24 for hyperopic patients. Mean preoperative IOP was 14.2+/-2.7 mmHg, and mean postoperative IOP was 13.46+/-2.1 mmHg over all follow-up investigations. The main complication was the development of subcapsular anterior opacifications of the crystalline lens in 25 eyes (33.3%), 2 of which showed direct contact to the ICL. Eleven eyes (14.7%) were stable in opacification and 14 eyes (18.7%) had progressive opacifications. The median time to opacification was 27.1 months. In 8 patients (10.7%), the subjective visual impairment mandated cataract surgery. The most significant long-term complication after ICL implantation is the formation of opacifications of the crystalline lens with the risk of the necessity of subsequent cataract surgery (10.7%). Old age, female gender, and contralateral opacification are independent significant risk factors for early formation of opacifications in this patient group.

The Fanconi anemia associated protein FAAP24 uses two substrate specific binding surfaces for DNA recognition

PubMed Central

Wienk, Hans; Slootweg, Jack C.; Speerstra, Sietske; Kaptein, Robert; Boelens, Rolf; Folkers, Gert E.

2013-01-01

To maintain the integrity of the genome, multiple DNA repair systems exist to repair damaged DNA. Recognition of altered DNA, including bulky adducts, pyrimidine dimers and interstrand crosslinks (ICL), partially depends on proteins containing helix-hairpin-helix (HhH) domains. To understand how ICL is specifically recognized by the Fanconi anemia proteins FANCM and FAAP24, we determined the structure of the HhH domain of FAAP24. Although it resembles other HhH domains, the FAAP24 domain contains a canonical hairpin motif followed by distorted motif. The HhH domain can bind various DNA substrates; using nuclear magnetic resonance titration experiments, we demonstrate that the canonical HhH motif is required for double-stranded DNA (dsDNA) binding, whereas the unstructured N-terminus can interact with single-stranded DNA. Both DNA binding surfaces are used for binding to ICL-like single/double-strand junction-containing DNA substrates. A structural model for FAAP24 bound to dsDNA has been made based on homology with the translesion polymerase iota. Site-directed mutagenesis, sequence conservation and charge distribution support the dsDNA-binding model. Analogous to other HhH domain-containing proteins, we suggest that multiple FAAP24 regions together contribute to binding to single/double-strand junction, which could contribute to specificity in ICL DNA recognition. PMID:23661679

Thermal comfort sustained by cold protective clothing in Arctic open-pit mining—a thermal manikin and questionnaire study

PubMed Central

JUSSILA, Kirsi; RISSANEN, Sirkka; AMINOFF, Anna; WAHLSTRÖM, Jens; VAKTSKJOLD, Arild; TALYKOVA, Ljudmila; REMES, Jouko; MÄNTTÄRI, Satu; RINTAMÄKI, Hannu

2017-01-01

Workers in the Arctic open-pit mines are exposed to harsh weather conditions. Employers are required to provide protective clothing for workers. This can be the outer layer, but sometimes also inner or middle layers are provided. This study aimed to determine how Arctic open-pit miners protect themselves against cold and the sufficiency, and the selection criteria of the garments. Workers’ cold experiences and the clothing in four Arctic open-pit mines in Finland, Sweden, Norway and Russia were evaluated by a questionnaire (n=1,323). Basic thermal insulation (Icl) of the reported clothing was estimated (ISO 9920). The Icl of clothing from the mines were also measured by thermal manikin (standing/walking) in 0.3 and 4.0 m/s wind. The questionnaire showed that the Icl of the selected clothing was on average 1.2 and 1.5 clo in mild (−5 to +5°C) and dry cold (−20 to −10°C) conditions, respectively. The Icl of the clothing measured by thermal manikin was 1.9–2.3 clo. The results show that the Arctic open-pit miners’ selected their clothing based on occupational (time outdoors), environmental (temperature, wind, moisture) and individual factors (cold sensitivity, general health). However, the selected clothing was not sufficient to prevent cooling completely at ambient temperatures below −10°C. PMID:29021416

NASA 60 GHz intersatellite communication link definition study. Baseline document

NASA Technical Reports Server (NTRS)

1986-01-01

The overall system and component concepts for a 60 GHz intersatellite communications link system (ICLS) are described. The ICLS was designed to augment the capabilities of the current Tracking and Data Relay Satellite System (TDRSS), providing a data rate capacity large enough to accommodate the expected rates for user satellites (USAT's) in the post-1995 timeframe. The use of 60 GHz for the anticipated successor to TDRSS, the Tracking and Data Acquisition System (TDAS), was selected because of current technology development that will enable multigigibit data rates. Additionally, the attenuation of the earth's atmosphere at 60 GHz means that there is virtually no possibility of terrestrially generated interference (intentional or accidental) or terrestrially based intercept. The ICLS includes the following functional areas: (1) the ICLS payload package on the GEO TDAS satellite that communicates simultaneously with up to five LEO USAT's; (2) the payload package on the USAT that communicates with the TDAS satellite; and (3) the crosslink payload package on the TDAS satellite that communicates with another TDAS satellite. Two methods of data relay on-board the TDAS spacecraft were addressed. One is a complete baseband system (demod and remod) with a bi-directional 2 Gbps data stream; the other is a channelized system wherein some of the channels are baseband and others are merely frequency translated before re-transmission. Descriptions of the TDAS antenna, transmitter, receiver, and mechanical designs are presented.

Soft shape-adaptive gripping device made from artificial muscle

NASA Astrophysics Data System (ADS)

Hamburg, E.; Vunder, V.; Johanson, U.; Kaasik, F.; Aabloo, A.

2016-04-01

We report on a multifunctional four-finger gripper for soft robotics, suitable for performing delicate manipulation tasks. The gripping device is comprised of separately driven gripping and lifting mechanisms, both made from a separate single piece of smart material - ionic capacitive laminate (ICL) also known as artificial muscle. Compared to other similar devices the relatively high force output of the ICL material allows one to construct a device able to grab and lift objects exceeding multiple times its own weight. Due to flexible design of ICL grips, the device is able to adapt the complex shapes of different objects and allows grasping single or multiple objects simultaneously without damage. The performance of the gripper is evaluated in two different configurations: a) the ultimate grasping strength of the gripping hand; and b) the maximum lifting force of the lifting actuator. The ICL is composed of three main layers: a porous membrane consisting of non-ionic polymer poly(vinylidene fluoride-co-hexafluoropropene) (PVdF-HFP), ionic liquid 1-ethyl-3-methylimidazolium trifluoromethane-sulfonate (EMITFS), and a reinforcing layer of woven fiberglass cloth. Both sides of the membrane are coated with a carbonaceous electrode. The electrodes are additionally covered with thin gold layers, serving as current collectors. Device made of this material operates silently, requires low driving voltage (<3 V), and is suitable for performing tasks in open air environment.

Structure of a DNA glycosylase that unhooks interstrand cross-links

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mullins, Elwood A.; Warren, Garrett M.; Bradley, Noah P.

DNA glycosylases are important editing enzymes that protect genomic stability by excising chemically modified nucleobases that alter normal DNA metabolism. These enzymes have been known only to initiate base excision repair of small adducts by extrusion from the DNA helix. However, recent reports have described both vertebrate and microbial DNA glycosylases capable of unhooking highly toxic interstrand cross-links (ICLs) and bulky minor groove adducts normally recognized by Fanconi anemia and nucleotide excision repair machinery, although the mechanisms of these activities are unknown. Here we report the crystal structure of Streptomyces sahachiroi AlkZ (previously Orf1), a bacterial DNA glycosylase that protectsmore » its host by excising ICLs derived from azinomycin B (AZB), a potent antimicrobial and antitumor genotoxin. AlkZ adopts a unique fold in which three tandem winged helix-turn-helix motifs scaffold a positively charged concave surface perfectly shaped for duplex DNA. Through mutational analysis, we identified two glutamine residues and a β-hairpin within this putative DNA-binding cleft that are essential for catalytic activity. Additionally, we present a molecular docking model for how this active site can unhook either or both sides of an AZB ICL, providing a basis for understanding the mechanisms of base excision repair of ICLs. Given the prevalence of this protein fold in pathogenic bacteria, this work also lays the foundation for an emerging role of DNA repair in bacteria-host pathogenesis.« less

Anion channel sensitivity to cytosolic organic acids implicates a central role for oxaloacetate in integrating ion flux with metabolism in stomatal guard cells.

PubMed

Wang, Yizhou; Blatt, Michael R

2011-10-01

Stomatal guard cells play a key role in gas exchange for photosynthesis and in minimizing transpirational water loss from plants by opening and closing the stomatal pore. The bulk of the osmotic content driving stomatal movements depends on ionic fluxes across both the plasma membrane and tonoplast, the metabolism of organic acids, primarily Mal (malate), and its accumulation and loss. Anion channels at the plasma membrane are thought to comprise a major pathway for Mal efflux during stomatal closure, implicating their key role in linking solute flux with metabolism. Nonetheless, little is known of the regulation of anion channel current (I(Cl)) by cytosolic Mal or its immediate metabolite OAA (oxaloacetate). In the present study, we have examined the impact of Mal, OAA and of the monocarboxylic acid anion acetate in guard cells of Vicia faba L. and report that all three organic acids affect I(Cl), but with markedly different characteristics and sidedness to their activities. Most prominent was a suppression of ICl by OAA within the physiological range of concentrations found in vivo. These findings indicate a capacity for OAA to co-ordinate organic acid metabolism with I(Cl) through the direct effect of organic acid pool size. The findings of the present study also add perspective to in vivo recordings using acetate-based electrolytes.

Evaluation of Simultaneous Nutrient and COD Removal with Polyhydroxybutyrate (PHB) Accumulation Using Mixed Microbial Consortia under Anoxic Condition and Their Bioinformatics Analysis

PubMed Central

Jena, Jyotsnarani; Kumar, Ravindra; Dixit, Anshuman; Pandey, Sony; Das, Trupti

2015-01-01

Simultaneous nitrate-N, phosphate and COD removal was evaluated from synthetic waste water using mixed microbial consortia in an anoxic environment under various initial carbon load (ICL) in a batch scale reactor system. Within 6 hours of incubation, enriched DNPAOs (Denitrifying Polyphosphate Accumulating Microorganisms) were able to remove maximum COD (87%) at 2g/L of ICL whereas maximum nitrate-N (97%) and phosphate (87%) removal along with PHB accumulation (49 mg/L) was achieved at 8 g/L of ICL. Exhaustion of nitrate-N, beyond 6 hours of incubation, had a detrimental effect on COD and phosphate removal rate. Fresh supply of nitrate-N to the reaction medium, beyond 6 hours, helped revive the removal rates of both COD and phosphate. Therefore, it was apparent that in spite of a high carbon load, maximum COD and nutrient removal can be maintained, with adequate nitrate-N availability. Denitrifying condition in the medium was evident from an increasing pH trend. PHB accumulation by the mixed culture was directly proportional to ICL; however the time taken for accumulation at higher ICL was more. Unlike conventional EBPR, PHB depletion did not support phosphate accumulation in this case. The unique aspect of all the batch studies were PHB accumulation was observed along with phosphate uptake and nitrate reduction under anoxic conditions. Bioinformatics analysis followed by pyrosequencing of the mixed culture DNA from the seed sludge revealed the dominance of denitrifying population, such as Corynebacterium, Rhodocyclus and Paraccocus (Alphaproteobacteria and Betaproteobacteria). Rarefaction curve indicated complete bacterial population and corresponding number of OTUs through sequence analysis. Chao1 and Shannon index (H’) was used to study the diversity of sampling. “UCI95” and “LCI95” indicated 95% confidence level of upper and lower values of Chao1 for each distance. Values of Chao1 index supported the results of rarefaction curve. PMID:25689047

Evaluation of simultaneous nutrient and COD removal with polyhydroxybutyrate (PHB) accumulation using mixed microbial consortia under anoxic condition and their bioinformatics analysis.

PubMed

Jena, Jyotsnarani; Kumar, Ravindra; Dixit, Anshuman; Pandey, Sony; Das, Trupti

2015-01-01

Simultaneous nitrate-N, phosphate and COD removal was evaluated from synthetic waste water using mixed microbial consortia in an anoxic environment under various initial carbon load (ICL) in a batch scale reactor system. Within 6 hours of incubation, enriched DNPAOs (Denitrifying Polyphosphate Accumulating Microorganisms) were able to remove maximum COD (87%) at 2 g/L of ICL whereas maximum nitrate-N (97%) and phosphate (87%) removal along with PHB accumulation (49 mg/L) was achieved at 8 g/L of ICL. Exhaustion of nitrate-N, beyond 6 hours of incubation, had a detrimental effect on COD and phosphate removal rate. Fresh supply of nitrate-N to the reaction medium, beyond 6 hours, helped revive the removal rates of both COD and phosphate. Therefore, it was apparent that in spite of a high carbon load, maximum COD and nutrient removal can be maintained, with adequate nitrate-N availability. Denitrifying condition in the medium was evident from an increasing pH trend. PHB accumulation by the mixed culture was directly proportional to ICL; however the time taken for accumulation at higher ICL was more. Unlike conventional EBPR, PHB depletion did not support phosphate accumulation in this case. The unique aspect of all the batch studies were PHB accumulation was observed along with phosphate uptake and nitrate reduction under anoxic conditions. Bioinformatics analysis followed by pyrosequencing of the mixed culture DNA from the seed sludge revealed the dominance of denitrifying population, such as Corynebacterium, Rhodocyclus and Paraccocus (Alphaproteobacteria and Betaproteobacteria). Rarefaction curve indicated complete bacterial population and corresponding number of OTUs through sequence analysis. Chao1 and Shannon index (H') was used to study the diversity of sampling. "UCI95" and "LCI95" indicated 95% confidence level of upper and lower values of Chao1 for each distance. Values of Chao1 index supported the results of rarefaction curve.

Posterior chamber phakic intraocular lens implantation: comparative, multicentre study in 351 eyes with low-to-moderate or high myopia.

PubMed

Kamiya, Kazutaka; Shimizu, Kimiya; Igarashi, Akihito; Kitazawa, Yoshihiro; Kojima, Takashi; Nakamura, Tomoaki; Oka, Yoshitaka; Matsumoto, Rei

2018-02-01

To compare the clinical outcomes of posterior chamber phakic intraocular lens implantation with a central hole (Hole Implantable Collamer Lens (ICL), STAAR Surgical) for low-to-moderate myopia and for high myopia. This multicentre retrospective case series comprised 351 eyes of 351 consecutive patients undergoing ICL implantation. Eyes were divided into groups based on preoperative degree of myopia: group 1; 57 eyes, manifest spherical equivalent less than -6 dioptres (D), and group 2; 294 eyes, -6 D or more. Safety, efficacy, predictability, stability and adverse events were compared preoperatively; and at 1 day, 1 week and 1, 3, 6 and 12 months postoperatively, RESULTS: Uncorrected and corrected visual acuities were -0.17±0.14 and -0.21±0.10 logMAR in group 1, and -0.16±0.09 and -0.21±0.08 logMAR in group 2, 1 year postoperatively. In groups 1 and 2, 98% and 99% of eyes were within 1.0 D of the targeted correction. Manifest refraction changes of -0.12±0.34 D (group 1) and -0.18±0.43 D (group 2) occurred from 1 day to 1 year. ICL exchanges were necessary in two eyes (0.7%) in group 2. No vision-threatening complications occurred at any time. The ICL performed well for the correction of both low-to-moderate myopia and high myopia throughout the 1-year observation period. The clinical outcomes of ICL implantation for low-to-moderate myopia are essentially equivalent to those for high myopia. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Effects of Implantable Collamer Lens V4c Placement on Iridocorneal Angle Measurements by Fourier-Domain Optical Coherence Tomography.

PubMed

Fernández-Vigo, José Ignacio; Macarro-Merino, Ana; Fernández-Vigo, Cristina; Fernández-Vigo, José Ángel; Martínez-de-la-Casa, José María; Fernández-Pérez, Cristina; García-Feijóo, Julián

2016-02-01

To assess by Fourier-domain optical coherence tomography (FDOCT) changes produced in iridocorneal angle measurements in patients undergoing Visian Implantable Collamer Lens (ICL) V4c (STAAR Surgical AG) placement. Prospective interventional case series. In 50 eyes of 25 myopic subjects consecutively scheduled for ICL implant, FDOCT (RTVue; Optovue Inc) iridocorneal angle measurements were made before and 1 and 3 months after surgery. Trabecular-iris angle (TIA) and angle opening distance 500 μm anterior to the scleral spur (AOD500) were compared among the quadrants nasal, temporal, and inferior, and correlations with ocular variables including lens vault were examined. Preoperative TIA was 48.7 ± 8.7, 48.2 ± 8.7, and 48.7 ± 9.3 degrees for the nasal, temporal, and inferior quadrants, with no differences (P = 1.000). Following ICL implant, corresponding values fell to 31.2 ± 11.5, 30.0 ± 10.7, and 29.7 ± 8.1 degrees at 1 month postsurgery, indicating angle narrowing of 34%-42%, and to 30.6 ± 12.3, 30.1 ± 11.9, and 29.8 ± 12.3 degrees, respectively, at 3 months postsurgery. Angle measurements failed to vary between 1 month and 3 months postsurgery (P = .481). In 8 eyes, iridotrabecular contact attributable to surgery was observed. One month after surgery, vault measurements correlated with TIA (R = -.309; P = .048). Six variables were identified as predictors of TIA at 1 month postsurgery (R(2) = .907). Although considerable angle narrowing was detected 1 month after ICL V4c implant, this narrowing remained stable at 3 months postsurgery. Factors predictive of TIA could serve to identify suitable candidates for ICL placement. Copyright © 2016 Elsevier Inc. All rights reserved.

Anti-Cancer Effects of Imperata cylindrica Leaf Extract on Human Oral Squamous Carcinoma Cell Line SCC-9 in Vitro.

PubMed

Keshava, Rohini; Muniyappa, Nagesh; Gope, Rajalakshmi; Ramaswamaiah, Ananthanarayana Saligrama

2016-01-01

Imperata cylindrica, a tall tufted grass which has multiple pharmacological applications is one of the key ingredients in various traditional medicinal formula used in India. Previous reports have shown that I. cylindrica plant extract inhibited cell proliferation and induced apoptosis in various cancer cell lines. To our knowledge, no studies have been published on the effect of I. cylindrica leaf extract on human oral cancers. The present study was undertaken in order to evaluate the anticancer properties of the leaf extract of I. cylindrica using an oral squamous cell carcinoma cell line SCC-9 as an in vitro model system. A methanol extract from dried leaves of I. cylindrica (ICL) was prepared by standard procedures. Effects of the ICL extract on the morphology of SCC-9 cells was visualized by microscopy. Cytotoxicity was determined by MTT assay. Effects of the ICL extract on colony forming ability of SCC-9 cells was evaluated using clonogenic assay. Cell cycle analysis was performed by flow cytometry and induction of apoptosis was determined by DNA fragmentation assay. The ICL extract treatment caused cytotoxicity and induced cell death in vitro in SCC-9 cells in a dose-dependent manner. This treatment also significantly reduced the clonogenic potential and inhibited cell proliferation by arresting the cell cycle in the G2/M phase. Furthermore, DNA fragmentation assays showed that the observed cell death was caused by apoptosis. This is the first report showing the anticancer activity of the methanol extracts from the leaves of I. cylindrica in human oral cancer cell line. Our data indicates that ICL extract could be considered as one of the lead compounds for the formulation of anticancer therapeutic agents to treat/manage human oral cancers. The natural abundance of I. cylindrica and its wide geographic distribution could render it one of the primary resource materials for preparation of anticancer therapeutic agents.

Protective Role of Acidic pH-Activated Chloride Channel in Severe Acidosis-Induced Contraction from the Aorta of Spontaneously Hypertensive Rats

PubMed Central

Ma, Zhiyong; Qi, Jia; Fu, Zhijie; Ling, Mingying; Li, Li; Zhang, Yun

2013-01-01

Severe acidic pH-activated chloride channel (ICl,acid) has been found in various mammalian cells. In the present study, we investigate whether this channel participates in reactions of the thoracic aorta to severe acidosis and whether it plays a role in hypertension. We measured isometric contraction in thoracic aorta rings from spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. Severe acidosis induced contractions of both endothelium-intact and -denuded thoracic aorta rings. In Wistar rats, contractions did not differ at pH 6.4, 5.4 and 4.4. However, in SHRs, contractions were higher at pH 5.4 or 4.4 than pH 6.4, with no difference between contractions at pH 5.4 and 4.4. Nifedipine, ICl,acid blockers 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and 4,4′-diisothiocyanatostilbene-2, 2′-disulfonic acid (DIDS) inhibited severe acidosis-induced contraction of aortas at different pH levels. When blocking ICl,acid, the remnant contraction was greater at pH 4.4 than pH 5.4 and 6.4 for both SHRs and Wistar rats. With nifedipine, the remnant contraction was greatly reduced at pH 4.4 as compared with at pH 6.4 and 5.4. With NPPB or DIDS, the ratio of remnant contractions at pH 4.4 and 5.4 (R4.4/5.4) was lower for SHRs than Wistar rats (all <1). However, with nifedipine, the R4.4/5.4 was higher for SHRs than Wistar rats (both >1). Furthermore, patch clamp recordings of ICl,acid and intracellular Ca2+ measurements in smooth muscle cells confirmed these findings. ICl,acid may protect arteries against excess vasoconstriction under extremely acidic extracellular conditions. This protective effect may be decreased in hypertension. PMID:23580361

Properties of the calcium-activated chloride current in heart.

PubMed

Zygmunt, A C; Gibbons, W R

1992-03-01

We used the whole cell patch clamp technique to study transient outward currents of single rabbit atrial cells. A large transient current, IA, was blocked by 4-aminopyridine (4AP) and/or by depolarized holding potentials. After block of IA, a smaller transient current remained. It was completely blocked by nisoldipine, cadmium, ryanodine, or caffeine, which indicates that all of the 4AP-resistant current is activated by the calcium transient that causes contraction. Neither calcium-activated potassium current nor calcium-activated nonspecific cation current appeared to contribute to the 4AP-resistant transient current. The transient current disappeared when ECl was made equal to the pulse potential; it was present in potassium-free internal and external solutions. It was blocked by the anion transport blockers SITS and DIDS, and the reversal potential of instantaneous current-voltage relations varied with extracellular chloride as predicted for a chloride-selective conductance. We concluded that the 4AP-resistant transient outward current of atrial cells is produced by a calcium-activated chloride current like the current ICl(Ca) of ventricular cells (1991. Circulation Research. 68:424-437). ICl(Ca) in atrial cells demonstrated outward rectification, even when intracellular chloride concentration was higher than extracellular. When ICa was inactivated or allowed to recover from inactivation, amplitudes of ICl(Ca) and ICa were closely correlated. The results were consistent with the view that ICl(Ca) does not undergo independent inactivation. Tentatively, we propose that ICl(Ca) is transient because it is activated by an intracellular calcium transient. Lowering extracellular sodium increased the peak outward transient current. The current was insensitive to the choice of sodium substitute. Because a recently identified time-independent, adrenergically activated chloride current in heart is reduced in low sodium, these data suggest that the two chloride currents are produced by different populations of channels.

Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening

PubMed Central

Abrahams, Garth L.; Kumar, Anuradha; Savvi, Suzana; Hung, Alvin W.; Wen, Shijun; Abell, Chris; Barry, Clifton E.; Sherman, David R.; Boshoff, Helena I.M.; Mizrahi, Valerie

2012-01-01

SUMMARY Whole-cell screening of Mycobacterium tuberculosis (Mtb) remains a mainstay of drug discovery but subsequent target elucidation often proves difficult. Conditional mutants that under-express essential genes have been used to identify compounds with known mechanism of action by target-based whole-cell screening (TB-WCS). Here, the feasibility of TB-WCS in Mtb was assessed by generating mutants that conditionally express pantothenate synthetase (panC), diaminopimelate decarboxylase (lysA) and isocitrate lyase (icl1). The essentiality of panC and lysA, and conditional essentiality of icl1 for growth on fatty acids, was confirmed. Depletion of PanC and Icl1 rendered the mutants hypersensitive to target-specific inhibitors. Stable reporter strains were generated for use in high-throughput screening, and their utility demonstrated by identifying compounds that display greater potency against a PanC-depleted strain. These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. PMID:22840772

Optical feedback cavity-enhanced absorption spectroscopy with a 3.24 μm interband cascade laser

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manfred, K. M.; Ritchie, G. A. D.; Lang, N.

2015-06-01

The development of interband cascade lasers (ICLs) has made the strong C-H transitions in the 3 μm spectral region increasingly accessible. We present the demonstration of a single mode distributed feedback ICL coupled to a V-shaped optical cavity in an optical feedback cavity-enhanced absorption spectroscopy (OF-CEAS) experiment. We achieved a minimum detectable absorption coefficient, α{sub min}, of (7.1±0.2)×10{sup −8} cm{sup −1} for a spectrum of CH{sub 4} at 3.24 μm with a two second acquisition time (100 scans averaged). This corresponds to a detection limit of 3 ppb CH{sub 4} at atmospheric pressure, which is comparable to previously reported OF-CEAS instruments with diodemore » lasers or quantum cascade lasers. The ability to frequency lock an ICL source in the important 3 μm region to an optical cavity holds great promise for future spectroscopic applications.« less

Upper limb load as a function of repetitive task parameters: part 1--a model of upper limb load.

PubMed

Roman-Liu, Danuta

2005-01-01

The aim of the study was to develop a theoretical indicator of upper limb musculoskeletal load based on repetitive task parameters. As such the dimensionless parameter, Integrated Cycle Load (ICL) was accepted. It expresses upper limb load which occurs during 1 cycle. The indicator is based on a model of a repetitive task, which consists of a model of the upper limb, a model of basic types of upper limb forces and a model of parameters of a repetitive task such as length of the cycle, length of periods of the cycle and external force exerted during each of the periods of the cycle. Calculations of the ICL parameter were performed for 12 different variants of external load characterised by different values of repetitive task parameters. A comparison of ICL, which expresses external load with a physiological indicator of upper limb load, is presented in Part 2 of the paper.

Multiple repair pathways mediate tolerance to chemotherapeutic cross-linking agents in vertebrate cells.

PubMed

Nojima, Kuniharu; Hochegger, Helfrid; Saberi, Alihossein; Fukushima, Toru; Kikuchi, Koji; Yoshimura, Michio; Orelli, Brian J; Bishop, Douglas K; Hirano, Seiki; Ohzeki, Mioko; Ishiai, Masamichi; Yamamoto, Kazuhiko; Takata, Minoru; Arakawa, Hiroshi; Buerstedde, Jean-Marie; Yamazoe, Mitsuyoshi; Kawamoto, Takuo; Araki, Kasumi; Takahashi, Jun A; Hashimoto, Nobuo; Takeda, Shunichi; Sonoda, Eiichiro

2005-12-15

Cross-linking agents that induce DNA interstrand cross-links (ICL) are widely used in anticancer chemotherapy. Yeast genetic studies show that nucleotide excision repair (NER), Rad6/Rad18-dependent postreplication repair, homologous recombination, and cell cycle checkpoint pathway are involved in ICL repair. To study the contribution of DNA damage response pathways in tolerance to cross-linking agents in vertebrates, we made a panel of gene-disrupted clones from chicken DT40 cells, each defective in a particular DNA repair or checkpoint pathway, and measured the sensitivities to cross-linking agents, including cis-diamminedichloroplatinum (II) (cisplatin), mitomycin C, and melphalan. We found that cells harboring defects in translesion DNA synthesis (TLS), Fanconi anemia complementation groups (FANC), or homologous recombination displayed marked hypersensitivity to all the cross-linking agents, whereas NER seemed to play only a minor role. This effect of replication-dependent repair pathways is distinctively different from the situation in yeast, where NER seems to play a major role in dealing with ICL. Cells deficient in Rev3, the catalytic subunit of TLS polymerase Polzeta, showed the highest sensitivity to cisplatin followed by fanc-c. Furthermore, epistasis analysis revealed that these two mutants work in the same pathway. Our genetic comprehensive study reveals a critical role for DNA repair pathways that release DNA replication block at ICLs in cellular tolerance to cross-linking agents and could be directly exploited in designing an effective chemotherapy.

HCl yield and chemical kinetics study of the reaction of Cl atoms with CH3I at the 298K temperature using the infra-red tunable diode laser absorption spectroscopy.

PubMed

Sharma, R C; Blitz, M; Wada, R; Seakins, P W

2014-07-15

Pulsed ArF excimer laser (193 nm)-CW infrared (IR) tunable diode laser Herriott type absorption spectroscopic technique has been made for the detection of product hydrochloric acid HCl. Absorption spectroscopic technique is used in the reaction chlorine atoms with methyl iodide (Cl+CH3I) to the study of kinetics on reaction Cl+CH3I and the yield of (HCl). The reaction of Cl+CH3I has been studied with the support of the reaction Cl+C4H10 (100% HCl) at temperature 298 K. In the reaction Cl+CH3I, the total pressure of He between 20 and 125 Torr at the constant concentration of [CH3I] 7.0×10(14) molecule cm(-3). In the present work, we estimated adduct formation is very important in the reaction Cl+CH3I and reversible processes as well and CH3I molecule photo-dissociated in the methyl [CH3] radical. The secondary chemistry has been studied as CH3+CH3ICl = product, and CH3I+CH3ICl = product2. The system has been modeled theoretically for secondary chemistry in the present work. The calculated and experimentally HCl yield nearly 65% at the concentration 1.00×10(14) molecule cm(-3) of [CH3I] and 24% at the concentration 4.0×10(15) molecule cm(-3) of [CH3I], at constant concentration 4.85×10(12) molecule cm(-3) of [CH3], and at 7.3×10(12) molecule cm(-3) of [Cl]. The pressure dependent also studied product of HCl at the constant [CH3], [Cl] and [CH3I]. The experimental results are also very good matching with the modelling work at the reaction CH3+CH3ICl = product (k = (2.75±0.35)×10(-10) s(-1)) and CH3I+CH3ICl = product2 (k = 1.90±0.15)×10(-12) s(-1). The rate coefficients of the reaction CH3+CH3ICl and CH3I+CH3ICl has been made in the present work. The experimental results has been studied by two method (1) phase locked and (2) burst mode. Copyright © 2014 Elsevier B.V. All rights reserved.

The outer regions of the giant Virgo galaxy M 87 Kinematic separation of stellar halo and intracluster light

NASA Astrophysics Data System (ADS)

Longobardi, Alessia; Arnaboldi, Magda; Gerhard, Ortwin; Hanuschik, Reinhard

2015-07-01

Aims: We present a spectroscopic study of a sample of 287 planetary nebulas (PNs) around the brightest cluster galaxy (BCG) M 87 in Virgo A, of which 211 are located between 40 kpc and 150 kpc from the galaxy centre. With these data we can distinguish the stellar halo from the co-spatial intracluster light (ICL) and study both components separately. Methods: We obtained PN velocities with a high resolution FLAMES/VLT survey targeting eight fields in a total area of ~0.4 deg2. We identified PNs from their narrow and symmetric redshifted λ5007 Å [OIII] emission line, the presence of the second λ4959 Å [OIII] emission line, and the absence of significant continuum. We implement a robust technique to measure the halo velocity dispersion from the projected phase-space to identify PNs associated with the M 87 halo and ICL. Using photometric magnitudes, we construct PN luminosity functions (PNLFs), which are complete down to m5007 = 28.8. Results: The velocity distribution of the spectroscopically confirmed PNs is bimodal, containing a narrow component centred on the systemic velocity of the BCG and an off-centred broader component, which we identify as halo and ICL, respectively. We find that 243 PNs are part of the velocity distribution of the M 87 halo, while the remaining subsample of 44 PNs are intracluster PNs (ICPNs). Halo and ICPNs have different spatial distributions: the number density of halo PNs follow the galaxy's surface brightness profile, whereas the ICPNs are characterised by a shallower power-law profile, IICL ∝ Rγ with γ in the range [-0.34, -0.04 ]. No evidence is found for an asymmetry in the halo and ICPN density distributions when the NW and SE fields are studied separately. A study of the composite PN number density profile confirms the superposition of different PN populations associated with the M 87 halo and the ICL, characterised by different PN specific numbers α. We derive αhalo = 1.06 × 10-8NPN L⊙,bol-1 and αICL = 2.72 × 10-8NPN L⊙,bol-1, respectively. The M 87 halo PNLF has fewer bright PNs and a steeper slope towards faint magnitudes than the ICPNLF, and both are steeper than the standard PNLF for the M 31 bulge. Moreover, the ICPNLF has a dip at ~1-1.5 mag fainter than the bright cut-off, reminiscent of the PNLFs of systems with extended star formation history, such as M 33 or the Magellanic clouds. Conclusions: The BCG halo of M 87 and the Virgo ICL are dynamically distinct components with different density profiles and velocity distributions. Moreover, the different α-parameter values and PNLF shapes of the halo and ICL indicate distinct parent stellar populations, consistent with the existence of a gradient towards bluer colours at large radii. These results reflect the hierarchical build-up of the Virgo cluster. Based on observations made with the VLT at Paranal Observatory under programs 088.B-0288(A) and 093.B-066(A), and with the SUBARU Telescope under program S10A-039.

Comparison between toric and spherical phakic intraocular lenses combined with astigmatic keratotomy for high myopic astigmatism.

PubMed

Zheng, Lin-Yan; Zhu, Shuang-Qian; Su, Yan-Feng; Zou, Hu-Yong; Wang, Qin-Mei; Yu, A-Yong

2017-01-01

To compare the outcomes of a toric phakic intraocular lens (PIOL) and a spherical PIOL combined with astigmatic keratotomy (AK) for the correction of high myopic astigmatism. This study enrolled patients with high myopic astigmatism, including 30 eyes (22 patients) that received a toric PIOL implantation (TICL group), and 32 eyes (24 patients) that received combined AK and a spherical PIOL implantation (AK+ ICL group). The outcomes were compared between the two groups before surgery, and at the following time points after surgery: 1 week, 1, 3, 6 months, and 1, 2 years. Preoperatively, the mean manifest spherical equivalent (SE) was -14.14 ± 2.12 D in the TICL group and -14.83 ± 2.79 D in the AK + ICL group ( P  = 0.28), and the mean manifest refractive cylinder, -2.87 ± 1.09 D and -2.58 ± 0.85 D, respectively ( P  = 0.28). Two years postoperatively, the mean safety index was 1.53 ± 0.55 in the TICL group and 1.60 ± 0.70 in the AK + ICL group ( P  = 1.00), and the mean efficacy index, 1.18 ± 0.45 and 1.38 ± 0.52, respectively ( P  = 0.86). The mean manifest refractive cylinder correction was 1.94 ± 1.07 D in the TICL group and 1.39 ± 0.71 D in the AK + ICL group ( P  = 0.02). The mean changes in SE and refractive cylinder from 1 week to 2 years were less than 0.50 D in both groups. Both TICL implantation and AK + ICL implantation are a good alternative for correction of astigmatism in addition to high myopia. TICL implantation has better predictability in correction of high myopic astigmatism. NCT03202485.

Four-year Follow-up of the Changes in Anterior Segment After Phakic Collamer Lens Implantation.

PubMed

Lu, Yuanyuan; Yang, Na; Li, Xuedong; Kong, Jun

2017-06-01

To assess the changes and relationship in central vaulting, flare intensity, and crystalline lens thickness during a follow-up period of 4 years after implantable collamer lens (ICL) implantation in eyes with high myopia. Retrospective observational study. Ninety-eight eyes of 50 patients were followed up with routine measurements of central vaulting, crystalline lens thickness, endothelial cell density, and aqueous flare postoperatively. Data were analyzed by repeated-measures analysis of variance. The relationship between the annual change in crystal lens thickness after surgery and age was evaluated by Pearson correlation coefficient and linear regression. There was a continuous reduction in central vaulting and endothelial cell density as well as an increase in crystalline lens thickness in ICL eyes from 1 month onward to 5 years postoperatively (P < .001). Although the trend of variation during the individual visit period was accentuated, the variation turned out to be smaller between 12 and 36 months or 60 months postoperatively (P = .42, P = .65). Aqueous flare intensity increased significantly after surgery and returned to normal 1 year later. Additionally, a positive correlation between patient age and crystalline lens thickness (r = 0.617, P < .0001) was observed in eyes with ICL implantation. The changes in central vaulting, endothelial cell density, and crystalline lens thickness are more prominent during the first year after ICL implantation, tending to be relatively stable afterwards. The anterior inflammation during the early postoperative period synchronizes with the sharp progression of crystalline lens changes within the first year. Copyright © 2017 Elsevier Inc. All rights reserved.

Acquisition of relative interstrand crosslinker resistance and PARP inhibitor sensitivity in Fanconi anemia head and neck cancers

PubMed Central

Lombardi, Anne J.; Hoskins, Elizabeth E.; Foglesong, Grant D.; Wikenheiser-Brokamp, Kathryn A.; Wiesmüller, Lisa; Hanenberg, Helmut; Andreassen, Paul R.; Jacobs, Allison J.; Olson, Susan B.; Keeble, Winifred W.; Hays, Laura E.; Wells, Susanne I.

2015-01-01

Purpose Fanconi anemia (FA) is an inherited disorder associated with a constitutional defect in the FA DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with FA are predisposed to formation of head and neck squamous cell carcinomas (HNSCCs) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Experimental Design Using HNSCC cell lines derived from the tumors of FA patients, and murine HNSCC cell lines derived from the tumors of wild type and Fancc−/− mice, we sought to define FA-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of FA HNSCC cells for non-homologous end joining (NHEJ). Results Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily FA-dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in FA cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by poly(ADP-ribose) polymerase (PARP) in FA-deficient cells. Moreover, human and murine FA HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by FA gene complementation. Conclusions The observed reliance upon PARP-mediated mechanisms reveals a means by which FA HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual. PMID:25609062

Idiopathic CD4 lymphocytopenia: Pathogenesis, etiologies, clinical presentations and treatment strategies.

PubMed

Yarmohammadi, Hale; Cunningham-Rundles, Charlotte

2017-10-01

Idiopathic CD4 lymphocytopenia (ICL) is a rare condition characterized by an unexplained deficit of circulating CD4 T cells leading to increased risk of serious opportunistic infections. The pathogenesis, etiology, clinical presentation, and best treatment options remain unclear. To describe the clinical presentation, treatment strategies, and outcome of patients with ICL seen in a single referral center. In a retrospective study, from January 1993 to January 2014, the demographic characteristics, clinical presentation, and treatments of patients diagnosed with ICL were reviewed. Twenty-four patients (14 female [58%] and 10 male [42%]) were evaluated. The mean age was 45 ± 17.6 years (range 7-76 years). Mean CD4 and CD8 T-cell counts at the time of diagnosis were 119 ± 84/mm 3 (range 4-294/mm 3 ) and 219 ± 258/mm 3 (range 7-630/mm 3 ), respectively. Seventeen patients (71%) had opportunistic infections, 4 (17%) had malignancies, and 3 (13%) had unexplained demyelinating disease and neurologic problems. Most patients had normal levels of immunoglobulins. Thirteen patients had abnormally low to absent response to phytohemagglutinin, concanavalin A, and antigens (candida and tetanus). Three patients had resolution of warts and 1 had mycobacterial lung infection on interleukin-2 with increases in CD4 count. The 11 patients on trimethoprim and sulfamethoxazole had no further hospital admissions for infections. The pathogenesis of ICL remains unclear. Although only some patients are healthy, most patients present with opportunistic infections. There is no known standard treatment aside from prophylactic antibiotics. Copyright © 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Immunoreactive LH in long-term frozen human urine samples.

PubMed

Singh, Gurmeet Kaur Surindar; Jimenez, Mark; Newman, Ron; Handelsman, David J

2014-04-01

Urine provides a convenient non-invasive alternative to blood sampling for measurement of certain hormones. Urinary luteinizing hormone (LH) measurements have been used for endocrinology research and anti-doping testing. However, the commercially available LH immunoassays are developed and validated for human blood samples but not urine so that LH assays intended for use with urine samples need thorough validation. Therefore, the present study evaluated the measurement of urinary LH immunoreactivity using previously validated immunofluorometric (IF) and immunochemiluminometric (ICL) LH assays after prolonged frozen storage. LH was measured in serial urine samples following administration of a single injection of one of two doses of recombinant human chorionic hormone (rhCG) with assays run at the end of study (2008) and again after four years of frozen (-20 °C) storage where samples were stored without adding preservatives. The ICL assay showed quantitatively reproducible LH measurements after prolonged -20 °C storage. However, the IF immunoassay gave consistently lower LH levels relative to ICL (2008) with a further proportionate reduction after four years of sample storage (2012). Yet, both the assays displayed similar patterns of the time-course of urine LH measurement both before and after four years of frozen storage. In conclusion, we found that both immunoassays are suitable for urinary LH measurements with ICL assay being more robust for quantitative urinary LH measurement such as for anti-doping purposes, whereas the IF could be applicable for research studies where urine LH levels are compared within-study but not in absolute terms. Copyright © 2013 John Wiley & Sons, Ltd.

Solvent isotope-induced equilibrium perturbation for isocitrate lyase.

PubMed

Quartararo, Christine E; Hadi, Timin; Cahill, Sean M; Blanchard, John S

2013-12-23

Isocitrate lyase (ICL) catalyzes the reversible retro-aldol cleavage of isocitrate to generate glyoxylate and succinate. ICL is the first enzyme of the glyoxylate shunt, which allows for the anaplerosis of citric acid cycle intermediates under nutrient limiting conditions. In Mycobacterium tuberculosis, the source of ICL for these studies, ICL is vital for the persistence phase of the bacterium's life cycle. Solvent kinetic isotope effects (KIEs) in the direction of isocitrate cleavage ((D₂O)V = 2.0 ± 0.1, and (D₂O)[V/K(isocitrate)] = 2.2 ± 0.3) arise from the initial deprotonation of the C2 hydroxyl group of isocitrate or the protonation of the aci-acid of the succinate product of the isocitrate aldol cleavage by a solvent-derived proton. This KIE suggested that an equilibrium mixture of all protiated isocitrate, glyoxylate, and succinate prepared in D₂O would undergo transient changes in equilibrium concentrations as a result of the solvent KIE and solvent-derived deuterium incorporation into both succinate and isocitrate. No change in the isotopic composition of glyoxylate was expected or observed. We have directly monitored the changing concentrations of all isotopic species of all reactants and products using a combination of nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry. Continuous monitoring of glyoxylate by ¹H NMR spectroscopy shows a clear equilibrium perturbation in D₂O. The final equilibrium isotopic composition of reactants in D₂O revealed dideuterated succinate, protiated glyoxylate, and monodeuterated isocitrate, with the transient appearance and disappearance of monodeuterated succinate. A model for the equilibrium perturbation of substrate species and their time-dependent isotopic composition is presented.

Ubiquitin-like protein UBL5 promotes the functional integrity of the Fanconi anemia pathway.

PubMed

Oka, Yasuyoshi; Bekker-Jensen, Simon; Mailand, Niels

2015-05-12

Ubiquitin and ubiquitin-like proteins (UBLs) function in a wide array of cellular processes. UBL5 is an atypical UBL that does not form covalent conjugates with cellular proteins and which has a known role in modulating pre-mRNA splicing. Here, we report an unexpected involvement of human UBL5 in promoting the function of the Fanconi anemia (FA) pathway for repair of DNA interstrand crosslinks (ICLs), mediated by a specific interaction with the central FA pathway component FANCI. UBL5-deficient cells display spliceosome-independent reduction of FANCI protein stability, defective FANCI function in response to DNA damage and hypersensitivity to ICLs. By mapping the sequence determinants underlying UBL5-FANCI binding, we generated separation-of-function mutants to demonstrate that key aspects of FA pathway function, including FANCI-FANCD2 heterodimerization, FANCD2 and FANCI monoubiquitylation and maintenance of chromosome stability after ICLs, are compromised when the UBL5-FANCI interaction is selectively inhibited by mutations in either protein. Together, our findings establish UBL5 as a factor that promotes the functionality of the FA DNA repair pathway. © 2015 The Authors.

A new study of iodine complexes of oxidized gum arabic: An interaction between iodine monochloride and aldehyde groups.

PubMed

Ali, Akbar; Ganie, Showkat Ali; Mazumdar, Nasreen

2018-01-15

Gum arabic, a plant polysaccharide was oxidized with periodate to produce aldehyde groups by the cleavage of diols present in the sugar units. The oxidized gum was then iodinated with iodine monochloride (ICl) and the interaction between electrophilic iodine, I + and reactive carbonyl groups of the modified gum was studied.Results of titrimetric estimation performed to determine the extent of oxidation and aldehyde content in the oxidized gum showed that degree of oxidation ranged between 19.68-50.19% which was observed to increase with periodate concentration; the corresponding aldehyde content was calculated to be 5.15-40.42%. Different strengths of ICl were used to iodinate the oxidized gum and the iodine content of the complexes varied from 6.11-11.72% as determined by iodometric titration. Structure elucidation of the iodine complexes conclusively established the attachment of ICl molecules to CHO groups. A reaction scheme has been proposed suggesting an electrophilic addition of the reagent to the aldehyde groups, a mechanism that was also supported by iodide ion release studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Human FAN1 promotes strand incision in 5'-flapped DNA complexed with RPA.

PubMed

Takahashi, Daisuke; Sato, Koichi; Hirayama, Emiko; Takata, Minoru; Kurumizaka, Hitoshi

2015-09-01

Fanconi anaemia (FA) is a human infantile recessive disorder. Seventeen FA causal proteins cooperatively function in the DNA interstrand crosslink (ICL) repair pathway. Dual DNA strand incisions around the crosslink are critical steps in ICL repair. FA-associated nuclease 1 (FAN1) is a DNA structure-specific endonuclease that is considered to be involved in DNA incision at the stalled replication fork. Replication protein A (RPA) rapidly assembles on the single-stranded DNA region of the stalled fork. However, the effect of RPA on the FAN1-mediated DNA incision has not been determined. In this study, we purified human FAN1, as a bacterially expressed recombinant protein. FAN1 exhibited robust endonuclease activity with 5'-flapped DNA, which is formed at the stalled replication fork. We found that FAN1 efficiently promoted DNA incision at the proper site of RPA-coated 5'-flapped DNA. Therefore, FAN1 possesses the ability to promote the ICL repair of 5'-flapped DNA covered by RPA. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

The diagnosis and treatment of peripheral lymphedema: 2013 Consensus Document of the International Society of Lymphology.

PubMed

2013-03-01

This International Society of Lymphology (ISL) Consensus Document is the current revision of the 1995 Document for the evaluation and management of peripheral lymphedema (1) for discussion at the XXIV International Congress of Lymphology. It is based upon modifications: [A] suggested and published following the 1997 XVI International Congress of Lymphology (ICL) in Madrid, Spain (2) discussed at the 1999 XVII ICL in Chennai, India (3) and considered/ confirmed at the 2000 (ISL) Executive Committee meeting in Hinterzarten, Germany (4); [B] derived from integration of discussions and written comments obtained during and following the 2001 XVIII ICL in Genoa, Italy as modified at the 2003 ISL Executive Committee meeting in Cordoba, Argentina (5); [C] suggested from comments, criticisms, and rebuttals as published in the December 2004 issue of Lymphology (6); [D] discussed in both the 2005 XX ICL in Salvador, Brazil and the 2007 XXI ICL in Shanghai, China and modified at the 2008 Executive Committee Meeting in Naples, Italy (7,8); and [E] modified from discussions and written comments from the 2009 XXII ICL in Sydney, Australia, the 2011 XXIII ICL in Malmo, Sweden and 2012 Executive Committee Meetings. The document attempts to amalgamate the broad spectrum of protocols advocated worldwide for the diagnosis and treatment of peripheral lymphedema into a coordinated proclamation representing a "Consensus" of the international community. The document is not meant to override individual clinical considerations for problematic patients nor to stifle progress. It is also not meant to be a legal formulation from which variations define medical malpractice. The Society understands that in some clinics the method of treatment derives from national standards while in others access to medical equipment and supplies is limited, and therefore the suggested treatments are impractical. Adaptability and inclusiveness does come at the price that members can rightly be critical of what they see as vagueness or imprecision in definitions, qualifiers in the choice of words (e.g., the use of "may... perhaps... unclear", etc.) and mention (albeit without endorsement) of treatment options supported by limited hard data. Most members are frustrated by the reality that NO treatment method has really undergone a satisfactory meta-analysis (let alone rigorous, randomized, stratified, long-term, controlled study). With this understanding, the absence of definitive answers and optimally conducted clinical trials, and with emerging technologies and new approaches and discoveries on the horizon, some degree of uncertainty, ambiguity, and flexibility along with dissatisfaction with current lymphedema evaluation and management is appropriate and to be expected. We continue to struggle to keep the document concise while balancing the need for depth and details. With these considerations in mind, we believe that this latest version presents a Consensus that embraces the entire ISL membership, rises above national standards, identifies and stimulates promising areas for future research and represents the best judgment of the ISL membership on how to approach patients with peripheral lymphedema as of 2013. Therefore the document has been, and should continue to be, challenged and debated in the pages of Lymphology (e.g., as Letters to the Editor), and ideally will remain a continued focal point for robust discussion at local, national and international conferences in lymphology and related disciplines. We further anticipate as experience evolves and new ideas and technologies emerge that this "living document" will undergo further periodic revision and refinement as the practice and theories of medicine and specifically lymphology change and advance.

Acquisition of Relative Interstrand Crosslinker Resistance and PARP Inhibitor Sensitivity in Fanconi Anemia Head and Neck Cancers.

PubMed

Lombardi, Anne J; Hoskins, Elizabeth E; Foglesong, Grant D; Wikenheiser-Brokamp, Kathryn A; Wiesmüller, Lisa; Hanenberg, Helmut; Andreassen, Paul R; Jacobs, Allison J; Olson, Susan B; Keeble, Winifred W; Hays, Laura E; Wells, Susanne I

2015-04-15

Fanconi anemia is an inherited disorder associated with a constitutional defect in the Fanconi anemia DNA repair machinery that is essential for resolution of DNA interstrand crosslinks. Individuals with Fanconi anemia are predisposed to formation of head and neck squamous cell carcinomas (HNSCC) at a young age. Prognosis is poor, partly due to patient intolerance of chemotherapy and radiation requiring dose reduction, which may lead to early recurrence of disease. Using HNSCC cell lines derived from the tumors of patients with Fanconi anemia, and murine HNSCC cell lines derived from the tumors of wild-type and Fancc(-/-) mice, we sought to define Fanconi anemia-dependent chemosensitivity and DNA repair characteristics. We utilized DNA repair reporter assays to explore the preference of Fanconi anemia HNSCC cells for non-homologous end joining (NHEJ). Surprisingly, interstrand crosslinker (ICL) sensitivity was not necessarily Fanconi anemia-dependent in human or murine cell systems. Our results suggest that the increased Ku-dependent NHEJ that is expected in Fanconi anemia cells did not mediate relative ICL resistance. ICL exposure resulted in increased DNA damage sensing and repair by PARP in Fanconi anemia-deficient cells. Moreover, human and murine Fanconi anemia HNSCC cells were sensitive to PARP inhibition, and sensitivity of human cells was attenuated by Fanconi anemia gene complementation. The observed reliance upon PARP-mediated mechanisms reveals a means by which Fanconi anemia HNSCCs can acquire relative resistance to the ICL-based chemotherapy that is a foundation of HNSCC treatment, as well as a potential target for overcoming chemoresistance in the chemosensitive individual. ©2015 American Association for Cancer Research.

Solvent Isotope-induced Equilibrium Perturbation for Isocitrate Lyase

PubMed Central

Quartararo, Christine E.; Hadi, Timin; Cahill, Sean M.; Blanchard, John S.

2014-01-01

Isocitrate lyase (ICL) catalyzes the reversible retro-aldol cleavage of isocitrate to generate glyoxylate and succinate. ICL is the first enzyme of the glyoxylate shunt, which allows for the anaplerosis of citric acid cycle intermediates under nutrient limiting conditions. In Mycobacterium tuberculosis, the source of ICL for these studies, ICL is vital for the persistence phase of the bacteria’s life cycle. Solvent kinetic isotope effects (KIEs) in the direction of isocitrate cleavage of D2OV = 2.0 ± 0.1 and D2O[V/Kisocitrate] = 2.2 ± 0.3 arise from the initial deprotonation of the C2 hydroxyl group of isocitrate or the protonation of the aci-acid of succinate product of the isocitrate aldol cleavage by a solvent-derived proton. This KIE suggested that an equilibrium mixture of all protiated isocitrate, glyoxylate and succinate prepared in D2O, would undergo transient changes in equilibrium concentrations as a result of the solvent KIE and solvent-derived deuterium incorporation into both succinate and isocitrate. No change in the isotopic composition of glyoxylate was expected or observed. We have directly monitored the changing concentrations of all isotopic species of all reactants and products using a combination of NMR spectroscopy and mass spectrometry. Continuous monitoring of glyoxylate by 1H NMR spectroscopy shows a clear equilibrium perturbation in D2O. The final equilibrium isotopic composition of reactants in D2O revealed di-deuterated succinate, protiated glyoxylate, and mono-deuterated isocitrate, with the transient appearance and disappearance of mono-deuterated succinate. A model for the equilibrium perturbation of substrate species, and their time-dependent isotopic composition is presented. PMID:24261638

A denuder-impinger system with in situ derivatization followed by gas chromatography-mass spectrometry for the determination of gaseous iodine-containing halogen species.

PubMed

Huang, Ru-Jin; Hoffmann, Thorsten

2008-11-14

Reactive iodine species have been suggested to play an important role in the atmosphere (e.g. tropospheric ozone depletion, coastal new particle formation). However, there still exist major uncertainties about their atmospheric chemistry, mostly due to the lack of analytical approaches for the accurate speciation of certain key compounds. In this study, 1,3,5-trimethoxybenzene (1,3,5-TMB)-coated denuder proved to be suitable for the differentiation between gaseous interhalogens (iodine monochloride (ICl), iodine monobromide (IBr)) and molecular iodine (I2) based on a selective collection/derivatization method. The results of the denuder sampling were compared with the results of impinger sampling in water, methanol and carbon tetrachloride solutions of 1,3,5-TMB. ICl and IBr are converted into 1-iodo-2,4,6-trimethoxybenzene (1-iodo-2,4,6-TMB) and 1-bromo-2,4,6-trimethoxybenzene (1-bromo-2,4,6-TMB), respectively, in the denuder systems. The respective collection efficiency is 99.2% for ICl and 92.6% for IBr, at 500mLmin(-1) gas flow rate. The collection efficiency for I2 is lower than 1% in the same denuder system, but significantly increases to about 90% in the aqueous 1,3,5-TMB loaded impinger. The denuder-impinger coupled system was then used to differentiate and to collect the ICl, IBr and I2 gas mixtures, followed by gas chromatography-ion trap mass spectrometry (GC-MS) determination. The precision of the method is in general better than 9.1%. The parameters affecting denuder operation including sampling flow rate, sampling duration, and relative humidity have been evaluated. The presented method provides an attractive protocol for iodine species analysis for atmospheric chemistry research.

The SNM1B/APOLLO DNA nuclease functions in resolution of replication stress and maintenance of common fragile site stability.

PubMed

Mason, Jennifer M; Das, Ishita; Arlt, Martin; Patel, Neil; Kraftson, Stephanie; Glover, Thomas W; Sekiguchi, JoAnn M

2013-12-15

SNM1B/Apollo is a DNA nuclease that has important functions in telomere maintenance and repair of DNA interstrand crosslinks (ICLs) within the Fanconi anemia (FA) pathway. SNM1B is required for efficient localization of key repair proteins, such as the FA protein, FANCD2, to sites of ICL damage and functions epistatically to FANCD2 in cellular survival to ICLs and homology-directed repair. The FA pathway is also activated in response to replication fork stalling. Here, we sought to determine the importance of SNM1B in cellular responses to stalled forks in the absence of a blocking lesion, such as ICLs. We found that depletion of SNM1B results in hypersensitivity to aphidicolin, a DNA polymerase inhibitor that causes replication stress. We observed that the SNM1B nuclease is required for efficient localization of the DNA repair proteins, FANCD2 and BRCA1, to subnuclear foci upon aphidicolin treatment, thereby indicating SNM1B facilitates direct repair of stalled forks. Consistent with a role for SNM1B subsequent to recognition of the lesion, we found that SNM1B is dispensable for upstream events, including activation of ATR-dependent signaling and localization of RPA, γH2AX and the MRE11/RAD50/NBS1 complex to aphidicolin-induced foci. We determined that a major consequence of SNM1B depletion is a marked increase in spontaneous and aphidicolin-induced chromosomal gaps and breaks, including breakage at common fragile sites. Thus, this study provides evidence that SNM1B functions in resolving replication stress and preventing accumulation of genomic damage.

Fanconi anemia: a disorder defective in the DNA damage response.

PubMed

Kitao, Hiroyuki; Takata, Minoru

2011-04-01

Fanconi anemia (FA) is a cancer predisposition disorder characterized by progressive bone marrow failure, congenital developmental defects, chromosomal abnormalities, and cellular hypersensitivity to DNA interstrand crosslink (ICL) agents. So far mutations in 14 FANC genes were identified in FA or FA-like patients. These gene products constitute a common ubiquitin-phosphorylation network called the "FA pathway" and cooperate with other proteins involved in DNA repair and cell cycle control to repair ICL lesions and to maintain genome stability. In this review, we summarize recent exciting discoveries that have expanded our view of the molecular mechanisms operating in DNA repair and DNA damage signaling.

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection.

PubMed

Aron, Allegra T; Heffern, Marie C; Lonergan, Zachery R; Vander Wal, Mark N; Blank, Brian R; Spangler, Benjamin; Zhang, Yaofang; Park, Hyo Min; Stahl, Andreas; Renslo, Adam R; Skaar, Eric P; Chang, Christopher J

2017-11-28

Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release d-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.

NASA/GE Energy Efficient Engine low pressure turbine scaled test vehicle performance report

NASA Technical Reports Server (NTRS)

Bridgeman, M. J.; Cherry, D. G.; Pedersen, J.

1983-01-01

The low pressure turbine for the NASA/General Electric Energy Efficient Engine is a highly loaded five-stage design featuring high outer wall slope, controlled vortex aerodynamics, low stage flow coefficient, and reduced clearances. An assessment of the performance of the LPT has been made based on a series of scaled air-turbine tests divided into two phases: Block 1 and Block 2. The transition duct and the first two stages of the turbine were evaluated during the Block 1 phase from March through August 1979. The full five-stage scale model, representing the final integrated core/low spool (ICLS) design and incorporating redesigns of stages 1 and 2 based on Block 1 data analysis, was tested as Block 2 in June through September 1981. Results from the scaled air-turbine tests, reviewed herein, indicate that the five-stage turbine designed for the ICLS application will attain an efficiency level of 91.5 percent at the Mach 0.8/10.67-km (35,000-ft), max-climb design point. This is relative to program goals of 91.1 percent for the ICLS and 91.7 percent for the flight propulsion system (FPS).

Detection of medically important Candida species by absolute quantitation real-time polymerase chain reaction.

PubMed

Than, Leslie Thian Lung; Chong, Pei Pei; Ng, Kee Peng; Seow, Heng Fong

2015-01-01

The number of invasive candidiasis cases has risen especially with an increase in the number of immunosuppressed and immunocom promised patients. The early detection of Candida species which is specific and sensitive is important in determining the correct administration of antifungal drugs to patients. This study aims to develop a method for the detection, identification and quantitation of medically important Candida species through quantitative polymerase chain reaction (qPCR). The isocitrate lyase (ICL) gene which is not found in mammals was chosen as the target gene of real-time PCR. Absolute quantitation of the gene copy number was achieved by constructing the plasmid containing the ICL gene which is used to generate standard curve. Twenty fungal species, two bacterial species and human DNA were tested to check the specificity of the detection method. All eight Candida species were successfully detected, identified and quantitated based on the ICL gene. A seven-log range of the gene copy number and a minimum detection limit of 10(3) copies were achieved. A one-tube absolute quantification real-time PCR that differentiates medically important Candida species via individual unique melting temperature was achieved. Analytical sensitivity and specificity were not compromised.

Optimization of a Two Stage Pulse Tube Refrigerator for the Integrated Current Lead System

NASA Astrophysics Data System (ADS)

Maekawa, R.; Matsubara, Y.; Okada, A.; Takami, S.; Konno, M.; Tomioka, A.; Imayoshi, T.; Hayashi, H.; Mito, T.

2008-03-01

Implementation of a conventional current lead with a pulse tube refrigerator has been validated to be working as an Integrated Current Lead (ICL) system for the Superconducting Magnetic Energy Storage (SMES). Realization of the system is primarily accounted for the flexibility of a pulse tube refrigerator, which does not posses any mechanical piston and/or displacer. As for an ultimate version of the ICL system, a High Temperature Superconducting (HTS) lead links a superconducting coil with a conventional copper lead. To ensure the minimization of heat loads to the superconducting coil, a pulse tube refrigerator has been upgraded to have a second cooling stage. This arrangement reduces not only the heat loads to the superconducting coil but also the operating cost for a SMES system. A prototype two-stage pulse tube refrigerator, series connected arrangement, was designed and fabricated to satisfy the requirements for the ICL system. Operation of the first stage refrigerator is a four-valve mode, while the second stage utilizes a double inlet configuration to ensure its confined geometry. The paper discusses the optimization of second stage cooling to validate the conceptual design

[Management of financial resources of permanent education in health: challenge of the in-service learning integration committees].

PubMed

Ferraz, Fabiane; Backes, Vânia Marli Schubert; Mercado-Martinez, Francisco Javier; Feuerwerker, Laura Camargo Macruz; Lino, Mônica Motta

2013-06-01

Despite adhering to the dynamics established in the Management Pact, the use of financial resources of Permanent Education in Health (PEH) still features as a problem in Brazil. This study analyzes how the management of these financial resources by two Permanent In-Service Learning Integration Committees (ICLS) evolves in the State of Santa Catarina, Brazil. It involves a qualitative, participatory research study adapted from Paulo Freire's Thematic Research conducted with 56 members from two ICLS between May and December 2009. After setting up the research groups, the members participated in the stages of theme generation surveys, encoding, decoding, and critical exposition of the reality. Participant observation and dialogue were the main data collection techniques. The results indicate that the two ICLS are not dissimilar in terms of issues of management of resources destined for policy, with bureaucracy, the indefinition of forms of financial management and delays that permeate regional structures responsible for resource management being the main factors detected. The participants considered the elaboration of PEH actions in the management of financial resources at state level to be the main opportunities for change.

Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions

PubMed Central

Basourakos, Spyridon P.; Li, Likun; Aparicio, Ana M.; Corn, Paul G.; Kim, Jeri; Thompson, Timothy C.

2017-01-01

Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a “molecular landscape,” i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with ”BRCAness”, i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent–induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies. PMID:27978798

Combination Platinum-based and DNA Damage Response-targeting Cancer Therapy: Evolution and Future Directions.

PubMed

Basourakos, Spyridon P; Li, Likun; Aparicio, Ana M; Corn, Paul G; Kim, Jeri; Thompson, Timothy C

2017-01-01

Maintenance of genomic stability is a critical determinant of cell survival and is necessary for growth and progression of malignant cells. Interstrand crosslinking (ICL) agents, including platinum-based agents, are first-line chemotherapy treatment for many solid human cancers. In malignant cells, ICL triggers the DNA damage response (DDR). When the damage burden is high and lesions cannot be repaired, malignant cells are unable to divide and ultimately undergo cell death either through mitotic catastrophe or apoptosis. The activities of ICL agents, in particular platinum-based therapies, establish a "molecular landscape," i.e., a pattern of DNA damage that can potentially be further exploited therapeutically with DDR-targeting agents. If the molecular landscape created by platinum-based agents could be better defined at the molecular level, a systematic, mechanistic rationale(s) could be developed for the use of DDR-targeting therapies in combination/maintenance protocols for specific, clinically advanced malignancies. New therapeutic drugs such as poly(ADP-ribose) polymerase (PARP) inhibitors are examples of DDR-targeting therapies that could potentially increase the DNA damage and replication stress imposed by platinum-based agents in tumor cells and provide therapeutic benefit for patients with advanced malignancies. Recent studies have shown that the use of PARP inhibitors together with platinum-based agents is a promising therapy strategy for ovarian cancer patients with "BRCAness", i.e., a phenotypic characteristic of tumors that not only can involve loss-of-function mutations in either BRCA1 or BRCA2, but also encompasses the molecular features of BRCA-mutant tumors. On the basis of these promising results, additional mechanism-based studies focused on the use of various DDR-targeting therapies in combination with platinum-based agents should be considered. This review discusses, in general, (1) ICL agents, primarily platinum-based agents, that establish a molecular landscape that can be further exploited therapeutically; (2) multiple points of potential intervention after ICL agent-induced crosslinking that further predispose to cell death and can be incorporated into a systematic, therapeutic rationale for combination/ maintenance therapy using DDR-targeting agents; and (3) available agents that can be considered for use in combination/maintenance clinical protocols with platinum-based agents for patients with advanced malignancies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Stimulation of in vivo hepatic uptake and in vitro hepatic binding of (/sup 125/I)2-lodo-3,7,8-trichlorodibenzo-p-dioxin by the administration of agonist for the Ah receptor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Poland, A.; Teitelbaum, P.; Glover, E.

1989-07-01

(125I)2-lodo-3,7,8-trichlorodibenzo-p-dioxin ((125I)Cl3DpD), a radiolabeled, isosteric, analogue of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), was synthesized and used to study in vivo tissue localization and in vivo tissue binding. Twenty-four hours after the administration of a tracer dose (1 X 10(-10) mol/kg) of (125I) Cl3DpD to C57BL/6J mice, the hepatic concentration of radioactivity was 1-2% of the administered dose, whereas in mice pretreated with TCDD (1 X 10(-7) mol/kg), the hepatic accumulation of radiolabel was 25-30% of that administered. Liver homogenate from TCDD-treated mice bound 4 to 10 times more (125I)Cl3DpD than homogenate from control mice. The enhancement of in vivo uptake and in vitromore » tissue binding of (125I)Cl3DpD by TCDD administration was confined to liver and was not observed in other tissues examined, kidney, lung, spleen, small intestines, and muscle. The administration of TCDD to C57BL/6J mice produces dose-related stimulation of in vivo hepatic uptake of (125I)Cl3DpD, binding of radioligand to liver homogenate, and hepatic aryl hydrocarbon hydroxylase activity, with the dose for half-maximal stimulation, ED50, varying from 1.5 to 4.0 x 10(-9) mol/kg. In congenic C57BL/6J (Ahd/Ahd) mice, which express the lower affinity Ah receptor, the ED50 values for all three responses were shifted to approximately 10-fold higher doses. 3,3',4,4',5,5'-Hexabromobiphenyl, a weak agonist for the Ah receptor produced a dose-related stimulation of these three responses in C57BL/6J mice (ED50 values of approximately 5 X 10(-7) mol/kg), but was without effect in C57BL/6J (Ahd/Ahd) mice. Stimulation of vivo hepatic uptake and in vitro liver homogenate binding of (125I)Cl3DpD was produced by administration of Ah agonists, such as 2,3,7,8-tetrachlorodibenzofuran and beta-naphthoflavone, but inactive congeners and other compounds that do not act via the Ah receptor.« less

Psoriasis associated with idiopathic CD4+ T-cell lymphopenia: a regulatory T-cell defect?

PubMed

Baroudjian, B; Viguier, M; Battistella, M; Beneton, N; Pagès, C; Gener, G; Bégon, E; Bachelez, H

2014-07-01

Idiopathic CD4(+) lymphocytopenia (ICL) is a rare immunodeficiency syndrome of unknown origin for which the increased risks of opportunistic infections and of malignancies have been well established; however, skin dysimmune diseases, including psoriasis, have been scarcely reported up to now. We report herein the severe course of psoriasis in four patients with ICL, and show evidence for a defect in the skin recruitment of regulatory CD4(+) FoxP3(+) T cells. These data raise the apparent paradigm of the occurrence of a severe immunomediated disease together with a profound T-cell defect, a model that might also apply to other immune deficiencies associated with psoriasis. © 2014 British Association of Dermatologists.

On the modified active region design of interband cascade lasers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Motyka, M.; Ryczko, K.; Dyksik, M.

2015-02-28

Type II InAs/GaInSb quantum wells (QWs) grown on GaSb or InAs substrates and designed to be integrated in the active region of interband cascade lasers (ICLs) emitting in the mid infrared have been investigated. Optical spectroscopy, combined with band structure calculations, has been used to probe their electronic properties. A design with multiple InAs QWs has been compared with the more common double W-shaped QW and it has been demonstrated that it allows red shifting the emission wavelength and enhancing the transition oscillator strength. This can be beneficial for the improvements of the ICLs performances, especially when considering their long-wavelengthmore » operation.« less

FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair.

PubMed

Liu, Ting; Ghosal, Gargi; Yuan, Jingsong; Chen, Junjie; Huang, Jun

2010-08-06

Fanconi anemia (FA) is caused by mutations in 13 Fanc genes and renders cells hypersensitive to DNA interstrand cross-linking (ICL) agents. A central event in the FA pathway is mono-ubiquitylation of the FANCI-FANCD2 (ID) protein complex. Here, we characterize a previously unrecognized nuclease, Fanconi anemia-associated nuclease 1 (FAN1), that promotes ICL repair in a manner strictly dependent on its ability to accumulate at or near sites of DNA damage and that relies on mono-ubiquitylation of the ID complex. Thus, the mono-ubiquitylated ID complex recruits the downstream repair protein FAN1 and facilitates the repair of DNA interstrand cross-links.

Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.

PubMed

Sawyer, Sarah L; Tian, Lei; Kähkönen, Marketta; Schwartzentruber, Jeremy; Kircher, Martin; Majewski, Jacek; Dyment, David A; Innes, A Micheil; Boycott, Kym M; Moreau, Lisa A; Moilanen, Jukka S; Greenberg, Roger A

2015-02-01

Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS). We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families. ©2014 American Association for Cancer Research.

Immunization by intrabronchial administration to 1-week-old foals of an unmarked double gene disruption strain of Rhodococcus equi strain 103+.

PubMed

Pei, Yanlong; Nicholson, Vivian; Woods, Katharine; Prescott, John F

2007-11-15

Rhodococcus equi causes fatal granulomatous pneumonia in foals and immunocompromised animals and humans. However, there is no effective vaccine against this infection. In this study, the chromosomal genes isocitrate lyase (icl) and cholesterol oxidase (choE) were chosen as targets for mutation and assessment of the double mutant as an intrabronchial vaccine in 1-week-old foals. Using a modification of a suicide plasmid previously developed in this laboratory, we developed a choE-icl unmarked deletion mutant of R. equi strain 103+. Five 1-week-old foals were infected intrabronchially with the mutant and challenged intrabronchially with the parent, virulent, strain 2 weeks later. Three of the foals were protected against pneumonia caused by the virulent strain, but the other two foals developed pneumonia caused by the mutant strain during the post-challenge period. Since infection of 3-week-old foals by an icl mutant in an earlier study had shown complete attenuation of the strain, we conclude that a proportion of foals in the 1st week or so of life are predisposed to developing R. equi pneumonia because of an inability to mount an effective immune response. This has been suspected previously but this is the first time that this has been demonstrated experimentally.

β2-spectrin depletion impairs DNA damage repair

PubMed Central

Horikoshi, Nobuo; Pandita, Raj K.; Mujoo, Kalpana; Hambarde, Shashank; Sharma, Dharmendra; Mattoo, Abid R.; Chakraborty, Sharmistha; Charaka, Vijaya; Hunt, Clayton R.; Pandita, Tej K.

2016-01-01

β2-Spectrin (β2SP/SPTBN1, gene SPTBN1) is a key TGF-β/SMAD3/4 adaptor and transcriptional cofactor that regulates TGF-β signaling and can contribute to liver cancer development. Here we report that cells deficient in β2-Spectrin (β2SP) are moderately sensitive to ionizing radiation (IR) and extremely sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with IR or ICL agents (formaldehyde, cisplatin, camptothecin, mitomycin), β2SP deficient cells displayed a higher frequency of cells with delayed γ-H2AX removal and a higher frequency of residual chromosome aberrations. Following hydroxyurea (HU)-induced replication stress, β2SP-deficient cells displayed delayed disappearance of γ-H2AX foci along with defective repair factor recruitment (MRE11, CtIP, RAD51, RPA, and FANCD2) as well as defective restart of stalled replication forks. Repair factor recruitment is a prerequisite for initiation of DNA damage repair by the homologous recombination (HR) pathway, which was also defective in β2SP deficient cells. We propose that β2SP is required for maintaining genomic stability following replication fork stalling, whether induced by either ICL damage or replicative stress, by facilitating fork regression as well as DNA damage repair by homologous recombination. PMID:27248179

Perceived body discomfort and trunk muscle activity in three prolonged sitting postures

PubMed Central

Waongenngarm, Pooriput; Rajaratnam, Bala S.; Janwantanakul, Prawit

2015-01-01

[Purpose] This study aimed to investigate the perceived discomfort and trunk muscle activity in three different 1-hour sitting postures. [Subjects] A repeated-measures design study was conducted on 10 healthy subjects. [Methods] Each subject sat for an hour in three sitting postures (i.e., upright, slumped, and forward leaning sitting postures). Subjects rated perceived body discomfort using Borg’s CR-10 scale at the beginning and after 1 hour sitting. The electromyographic activity of the trunk muscle activity was recorded during the 1-hour period of sitting. [Results] The forward leaning sitting posture led to higher Borg scores in the low back than those in the upright (p = 0.002) and slumped sitting postures (p < 0.001). The forward leaning posture was significantly associated with increased iliocostalis lumborum pars thoracis (ICL) and superficial lumbar multifidus (MF) muscle activity compared with the upright and slumped sitting postures. The upright sitting posture was significantly associated with increased internal oblique (IO)/transversus abdominis (TrA) and ICL muscle activity compared with the slumped sitting posture. [Conclusion] The sitting posture with the highest low back discomfort after prolonged sitting was the forward leaning posture. Sitting in an upright posture is recommended because it increases IO/TrA muscle activation and induces only relatively moderate ICL and MF muscle activation. PMID:26311951

Psoralen-induced DNA adducts are substrates for the base excision repair pathway in human cells

PubMed Central

Couvé-Privat, Sophie; Macé, Gaëtane; Saparbaev, Murat K.

2007-01-01

Interstrand cross-link (ICL) is a covalent modification of both strands of DNA, which prevents DNA strand separation during transcription and replication. Upon photoactivation 8-methoxypsoralen (8-MOP+UVA) alkylates both strands of DNA duplex at the 5,6-double bond of thymidines, generating monoadducts (MAs) and ICLs. It was thought that bulky DNA lesions such as MAs are eliminated only in the nucleotide excision repair pathway. Instead, non-bulky DNA lesions are substrates for DNA glycosylases and AP endonucleases which initiate the base excision repair (BER) pathway. Here we examined whether BER might be involved in the removal of psoralen–DNA photoadducts. The results show that in human cells DNA glycosylase NEIL1 excises the MAs in duplex DNA, subsequently the apurinic/apyrimidinic endonuclease 1, APE1, removes the 3′-phosphate residue at single-strand break generated by NEIL1. The apparent kinetic parameters suggest that NEIL1 excises MAs with high efficiency. Consistent with these results HeLa cells lacking APE1 and/or NEIL1 become hypersensitive to 8-MOP+UVA exposure. Furthermore, we demonstrate that bacterial homologues of NEIL1, the Fpg and Nei proteins, also excise MAs. New substrate specificity of the Fpg/Nei protein family provides an alternative repair pathway for ICLs and bulky DNA damage. PMID:17715144

Compensated Cell Enlargement in fugu5 is Specifically Triggered by Lowered Sucrose Production from Seed Storage Lipids.

PubMed

Takahashi, Kazuki; Morimoto, Ryousuke; Tabeta, Hiromitsu; Asaoka, Mariko; Ishida, Masanori; Maeshima, Masayoshi; Tsukaya, Hirokazu; Ferjani, Ali

2017-04-01

To reveal the logic of size regulation in multicellular organisms, we have used Arabidopsis thaliana as a model organism and its leaves as a model organ. We discovered the existence of a compensatory system, whereby a decrease in leaf cell number often triggers unusual cell enlargement. However, despite the large number of compensation-exhibiting mutants analyzed to date, we have only a limited understanding of the detailed molecular mechanisms triggering the decrease in cell number and subsequent compensated cell enlargement (CCE). CCE in fugu5, the vacuolar type H+-pyrophosphatase loss-of-function mutant, is specific to cotyledons and completely suppressed when sucrose (Suc) is supplied or cytosolic pyrophosphate (PPi) is specifically removed. In addition, several lines of evidence suggest that excess cytosolic PPi in fugu5 impairs gluconeogenesis from triacylglycerol (TAG) to Suc. Here, detailed cellular phenotyping revealed that the loss-of-function mutants icl-2, mls-2 and pck1-2 triggered CCE in cotyledons. All double mutant combinations between fugu5-1 and the above three mutants exhibited compensation, but did not display a further increase in cell size. Importantly, similar phenotypes were observed in icl-2 mls-2, icl-2 pck1-2 and mls-2 pck1-2. Quantification of TAG breakdown and Suc contents further supported our findings. Taken together, we demonstrate that de novo Suc synthesis from TAG is fundamentally important for proper resumption of post-germinative cotyledon development. Moreover, provided that icl-2, mls-2 and pck1-2 are only compromised in Suc biosynthesis de novo from TAG, our findings clearly indicate that lowered Suc production in fugu5, rather than excess cytosolic PPi, is the direct trigger of CCE. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Determination of iodide with 1,3-dibromo-5,5-dimethylhydantoin (DBH) in comparison with the ICl-method. Analytical methods of pharmacopeias with DBH in respect to environmental and economical concern. Part 3.

PubMed

Hilp, M; Senjuk, S

2001-06-01

USP 1995 (The United States Pharmacopeia, 23rd Edit., (1995), potassium iodide p. 1265, sodium iodide p. 1424), PH. EUR. 1997 (European Pharmacopoeia, third ed., Council of Europe, Strasbourg, (1997), potassium iodide p. 1367, sodium iodide p. 1493) and JAP 1996 (The Japanes Pharmacopoeia, 13th ed. (1996), potassium iodide p. 578, sodium iodide p. 630) determine iodide with the ICl-method (J. Am. Chem. Soc. 25 (1903) 756-761; Z. Anorg. Chem. 36 (1903) 76-83; Fresenius Z. Anal. Chem. 106 (1936) 12-23; Arzneibuch-Kommentar, Wissenschaftliche Erläuterungen zum Europäischen Arzneibuch, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Govi-Verlag - Pharmazeutischer Verlag GmbH, Eschborn, 12th suppl. (1999), K10 p. 2), using chloroform, which is toxic and hazardous to environment. Without the application of chlorinated hydrocarbons USP 2000 (The United State Pharmacopeia, 24th ed. (2000), potassium iodide p. 1368, sodium iodide p. 1535) and Brit 1999 (British Pharmacopoeia London, (1999), Appendix VIII C, p. A162) titrate iodide with the redox indicator amaranth. A titration with potentiometric indication giving two end-points at the step of I(2) and [ICl(2)](-) is described. Due to the high concentration of hydrochloric acid required for the ICl-method, the determination with DBH (1,3-dibromo-5,5-dimethylhydantoin; 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione) can be recommended and is performed easily. Similarly, the iodide content of gallamine triethiodide may be analyzed with DBH by application of a visual two-phase titration in water and ethyl acetate or with potentiometric indication in a mixture of 2-propanol and water. During the removal of the excess of DBH 4-bromo-triethylgallamine (2,2',2"-[1-bromo-benzene-2,3,4-triyltris(oxy)]N,N,N-triethylethanium) is formed.

Use of inequality constrained least squares estimation in small area estimation

NASA Astrophysics Data System (ADS)

Abeygunawardana, R. A. B.; Wickremasinghe, W. N.

2017-05-01

Traditional surveys provide estimates that are based only on the sample observations collected for the population characteristic of interest. However, these estimates may have unacceptably large variance for certain domains. Small Area Estimation (SAE) deals with determining precise and accurate estimates for population characteristics of interest for such domains. SAE usually uses least squares or maximum likelihood procedures incorporating prior information and current survey data. Many available methods in SAE use constraints in equality form. However there are practical situations where certain inequality restrictions on model parameters are more realistic. It will lead to Inequality Constrained Least Squares (ICLS) estimates if the method used is least squares. In this study ICLS estimation procedure is applied to many proposed small area estimates.

Machine learning for epigenetics and future medical applications.

PubMed

Holder, Lawrence B; Haque, M Muksitul; Skinner, Michael K

2017-07-03

Understanding epigenetic processes holds immense promise for medical applications. Advances in Machine Learning (ML) are critical to realize this promise. Previous studies used epigenetic data sets associated with the germline transmission of epigenetic transgenerational inheritance of disease and novel ML approaches to predict genome-wide locations of critical epimutations. A combination of Active Learning (ACL) and Imbalanced Class Learning (ICL) was used to address past problems with ML to develop a more efficient feature selection process and address the imbalance problem in all genomic data sets. The power of this novel ML approach and our ability to predict epigenetic phenomena and associated disease is suggested. The current approach requires extensive computation of features over the genome. A promising new approach is to introduce Deep Learning (DL) for the generation and simultaneous computation of novel genomic features tuned to the classification task. This approach can be used with any genomic or biological data set applied to medicine. The application of molecular epigenetic data in advanced machine learning analysis to medicine is the focus of this review.

Photoionization studies with molecular beams

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ng, C.Y.

1976-09-01

A molecular beam photoionization apparatus which combines the advantages of both the molecular beam method with photoionization mass spectrometry has been designed and constructed for carrying out some unique photoionization experiments. Rotational cooling during the supersonic expansion has resulted in high resolution photoionization efficiency curves for NO, ICl, C/sub 2/H/sub 2/ and CH/sub 3/I. The analysis of these spectra has yielded ionization potentials for these molecules to an accuracy of +- 3 MeV. Detailed autoionization structures were also resolved. This allows the investigation of the selection rules for autoionization, and the identification of the Rydberg series which converge to themore » excited states of the molecular ions. The degree of relaxation for thermally populated excited states has been examined using NO and ICl as examples. As a result of adiabatic cooling, a small percentage of dimers is also formed during the expansion. The photoionization efficiency curves for (NO)/sub 2/, ArICl, Ar/sub 2/, Kr/sub 2/ and Xe/sub 2/ have been obtained near the thresholds. Using the known dissociation energies of the (NO)/sub 2/, Ar/sub 2/, Kr/sub 2/ and Xe/sub 2/ van der Waals molecules, the corresponding dissociation energies for NO-NO/sup +/, Ar/sub 2//sup +/, Kr/sub 2//sup +/, and Xe/sub 2//sup +/ have been determined. The ionization mechanisms for this class of molecules are examined and discussed.« less

AMP-activated protein kinase is involved in the activation of the Fanconi anemia/BRCA pathway in response to DNA interstrand crosslinks.

PubMed

Chun, Min Jeong; Kim, Sunshin; Hwang, Soo Kyung; Kim, Bong Sub; Kim, Hyoun Geun; Choi, Hae In; Kim, Jong Heon; Goh, Sung Ho; Lee, Chang-Hun

2016-08-16

Fanconi anemia complementation group (FANC) proteins constitute the Fanconi Anemia (FA)/BRCA pathway that is activated in response to DNA interstrand crosslinks (ICLs). We previously performed yeast two-hybrid screening to identify novel FANC-interacting proteins and discovered that the alpha subunit of AMP-activated protein kinase (AMPKα1) was a candidate binding partner of the FANCG protein, which is a component of the FA nuclear core complex. We confirmed the interaction between AMPKα and both FANCG using co-immunoprecipitation experiments. Additionally, we showed that AMPKα interacted with FANCA, another component of the FA nuclear core complex. AMPKα knockdown in U2OS cells decreased FANCD2 monoubiquitination and nuclear foci formation upon mitomycin C-induced ICLs. Furthermore, AMPKα knockdown enhanced cellular sensitivity to MMC. MMC treatment resulted in an increase in AMPKα phosphorylation/activation, indicating AMPK is involved in the cellular response to ICLs. FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway. Our data suggest AMPK is involved in the activation of the FA/BRCA pathway.

The novel choline kinase inhibitor ICL-CCIC-0019 reprograms cellular metabolism and inhibits cancer cell growth

PubMed Central

Trousil, Sebastian; Kaliszczak, Maciej; Schug, Zachary; Nguyen, Quang-De; Tomasi, Giampaolo; Favicchio, Rosy; Brickute, Diana; Fortt, Robin; Twyman, Frazer J.; Carroll, Laurence; Kalusa, Andrew; Navaratnam, Naveenan; Adejumo, Thomas; Carling, David; Gottlieb, Eyal; Aboagye, Eric O.

2016-01-01

The glycerophospholipid phosphatidylcholine is the most abundant phospholipid species of eukaryotic membranes and essential for structural integrity and signaling function of cell membranes required for cancer cell growth. Inhibition of choline kinase alpha (CHKA), the first committed step to phosphatidylcholine synthesis, by the selective small-molecule ICL-CCIC-0019, potently suppressed growth of a panel of 60 cancer cell lines with median GI50 of 1.12 μM and inhibited tumor xenograft growth in mice. ICL-CCIC-0019 decreased phosphocholine levels and the fraction of labeled choline in lipids, and induced G1 arrest, endoplasmic reticulum stress and apoptosis. Changes in phosphocholine cellular levels following treatment could be detected non-invasively in tumor xenografts by [18F]-fluoromethyl-[1,2–2H4]-choline positron emission tomography. Herein, we reveal a previously unappreciated effect of choline metabolism on mitochondria function. Comparative metabolomics demonstrated that phosphatidylcholine pathway inhibition leads to a metabolically stressed phenotype analogous to mitochondria toxin treatment but without reactive oxygen species activation. Drug treatment decreased mitochondria function with associated reduction of citrate synthase expression and AMPK activation. Glucose and acetate uptake were increased in an attempt to overcome the metabolic stress. This study indicates that choline pathway pharmacological inhibition critically affects the metabolic function of the cell beyond reduced synthesis of phospholipids. PMID:27206796

An Inequality Constrained Least-Squares Approach as an Alternative Estimation Procedure for Atmospheric Parameters from VLBI Observations

NASA Astrophysics Data System (ADS)

Halsig, Sebastian; Artz, Thomas; Iddink, Andreas; Nothnagel, Axel

2016-12-01

On its way through the atmosphere, radio signals are delayed and affected by bending and attenuation effects relative to a theoretical path in vacuum. In particular, the neutral part of the atmosphere contributes considerably to the error budget of space-geodetic observations. At the same time, space-geodetic techniques become more and more important in the understanding of the Earth's atmosphere, because atmospheric parameters can be linked to the water vapor content in the atmosphere. The tropospheric delay is usually taken into account by applying an adequate model for the hydrostatic component and by additionally estimating zenith wet delays for the highly variable wet component. Sometimes, the Ordinary Least Squares (OLS) approach leads to negative estimates, which would be equivalent to negative water vapor in the atmosphere and does, of course, not reflect meteorological and physical conditions in a plausible way. To cope with this phenomenon, we introduce an Inequality Constrained Least Squares (ICLS) method from the field of convex optimization and use inequality constraints to force the tropospheric parameters to be non-negative allowing for a more realistic tropospheric parameter estimation in a meteorological sense. Because deficiencies in the a priori hydrostatic modeling are almost fully compensated by the tropospheric estimates, the ICLS approach urgently requires suitable a priori hydrostatic delays. In this paper, we briefly describe the ICLS method and validate its impact with regard to station positions.

Stability of bromine, iodine monochloride, copper (II) chloride, and nickel (II) chloride intercalated pitch-based graphite fibers

NASA Technical Reports Server (NTRS)

Gaier, James R.; Slabe, Melissa E.; Shaffer, Nanette

1987-01-01

Four different grades of pitch-based graphite fibers (Amoco P-55, P-75, P-100. and P-120) were intercalated with each of four different intercalates: bromine (Br2), iodine monochloride (ICl), copper (II) chloride (CuCl2), and nickel (II) chloride (NiCl2). The P-55 fibers did not react with Br2 or NiCl2, and the P-75 did not react with NiCl2. The stability of the electrical resistance of the intercalated fibers was monitored over long periods of time in ambient, high humidity (100 percent at 60 C), vacuum (10 to the -6 torr), and high temperature (up to 400 C) conditions. Fibers with lower graphitization form graphite intercalation compounds (GIC's) which are more stable than those with higher graphitization (i.e., P-55 (most stable) greater than P-75 greater than P-100 greater than P-120 (least stable). Br2 formed the most stable GIC's followed in order of decreasing stability by ICl, CuCl2, and NiCl2. While Br2 GIC's had the most stability, ICl had the advantages of forming GIC's with slightly greater reduction in resistance (by about 10%) than Br2, and the ability to intercalate P-55 fiber. Transition metal chlorides are susceptible to water vapor and high temperature. The stability of fibers in composites differs.

Inertia critical layers and their impacts on nongeostrophic baroclinic instability

NASA Astrophysics Data System (ADS)

Shen, Bo-Wen

We investigate the effects of critical levels (CLs) on a baroclinic flow over mountains, nongeostrophic (NG) inertia critical layer instability, and NG baroclinic instability (BI) in a three-layer atmosphere with a small Richardson number (Ri) in the middle layer. We develop a numerical wave decomposition method in Chapter 2, which is found to be useful in determining the reflection coefficient (Ref) numerically when the flow system is too complicated to obtain Ref analytically. Effects of CLs on flow over mountains are studied both analytically and numerically in Chapter 3. We define the effective inertia critical level (ICL) as the height above which inertia-gravity waves attenuate significantly. Based on numerical simulations with a broad range of Rossby number (Ro) and Ri, four wave regimes are found: (a) Regime I: inertia- gravity waves. The flow behaves like unsheared inertia- gravity waves and the effective lower ICL plays a similar role as the classical critical level (CCL) does in a nonrotating flow. (b) Regime II: combined inertia-gravity waves and baroclinic lee waves. These waves behave like those in Regime I below the lower effective ICL, and like baroclinic lee waves near the CCL. (c) Regime III: combined evanescent and baroclinic lee waves. These waves still behave like baroclinic lee waves near the CCL, but are trapped near the surface. (d) Regime IV: transient waves. NG baroclinic instability exists, as evidenced by the positive domain-averaged north-south heat flux. Wave regime IV is further investigated in Chapter 5. We identify the NG baroclinic instability in Chapter 3 as an inertia critical layer (ICLY) instability. The role of the upper inertia critical level in this instability has been studied by choosing a periodic mountain. When only the CCL and upper ICL are present in the domain, the mesoscale ICLY instability tends to occur. For a periodic mountain ridge, the ICLY instability selects the mountain's tvavelength as its wavelength of maximum growth. For an isolated mountain ridge, the NG baroclinic lee wave is established in the beginning for flows with small Ri, which then develops its own upper ICL. The stability of Lindzen and Tung's (1976, hereafter LT76) type of three-layer nonrotating/rotating atmosphere is discussed in Chapter 6. We first investigate the transient dynamics of wave ducting by a numerical model. The adjustment time for waves to be ducted depends on the atmospheric structure and horizontal wavelength. Second, we study the effects of Coriolis force on LT76's wave ducting mechanism, and show that a wave with wavelength on the order of 100 km is hardly ducted. (Abstract shortened by UMI.)

Phakic Intraocular Collamer Lens (Visian ICL) Implantation for Correction of Myopia in Spectacle-Aversive Special Needs Children.

PubMed

Tychsen, Lawrence; Faron, Nicholas; Hoekel, James

2017-03-01

A subset of children with high anisometropia or isoametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral intraocular collamer lens (Visian ICL) implantation for moderate to high myopia. Prospective nonrandomized cohort study. Clinical course and outcome data were collated prospectively for 40 implanted eyes in 23 children (mean age 10.2 ± 5.3 years, range, 1.8-17 years). Myopia ranged from -3.0 to -14.5 diopters (D), mean -9.2 ± 3.5 D. Goal refraction was plano to +1 D. Correction was achieved by sulcus implantation of a Visian ICL (STAAR Surgical, Monrovia, California, USA) under general anesthesia. Mean follow-up was 15.1 months (range, 6-22 months). Thirty-five eyes (88%) were corrected to within ±1.0 D of goal refraction; the other 5 (12%) were corrected to within 1.5 D. Uncorrected distance visual acuity improved substantially in all eyes (from mean 20/1050 [logMAR 1.72] to mean 20/42 [logMAR 0.48]). Spherical regression at last follow-up was an average of +0.59 D. Visuomotor comorbidities (eg, amblyopia, nystagmus, foveopathy, optic neuropathy) accounted for residual postoperative subnormal visual acuity. Thirteen of the 23 children (57%) had a neurobehavioral disorder (eg, developmental delay/intellectual disability/mental retardation, Down syndrome, cerebral palsy, autism spectrum disorder). Eighty-five percent (11/13) of those children were reported to have enhanced visual awareness, attentiveness, or social interactions. Endothelial cell density was measureable in 6 cooperative children (10 eyes), showing an average 1% decline. Central corneal thickness, measured in all children, increased an average of 8 μm. Two children (8%) required unplanned return to the operating room on the first postoperative day to alleviate pupillary block caused by a nonpatent iridotomy. No other complications were encounterd. Visian ICL implantation improves visual function in special needs children who have moderate to high myopia and difficulties wearing glasses or contact lenses. Copyright © 2016 Elsevier Inc. All rights reserved.

Metabolic adaptation of two in silico mutants of Mycobacterium tuberculosis during infection.

PubMed

López-Agudelo, Víctor A; Baena, Andres; Ramirez-Malule, Howard; Ochoa, Silvia; Barrera, Luis F; Ríos-Estepa, Rigoberto

2017-11-21

Up to date, Mycobacterium tuberculosis (Mtb) remains as the worst intracellular killer pathogen. To establish infection, inside the granuloma, Mtb reprograms its metabolism to support both growth and survival, keeping a balance between catabolism, anabolism and energy supply. Mtb knockouts with the faculty of being essential on a wide range of nutritional conditions are deemed as target candidates for tuberculosis (TB) treatment. Constraint-based genome-scale modeling is considered as a promising tool for evaluating genetic and nutritional perturbations on Mtb metabolic reprogramming. Nonetheless, few in silico assessments of the effect of nutritional conditions on Mtb's vulnerability and metabolic adaptation have been carried out. A genome-scale model (GEM) of Mtb, modified from the H37Rv iOSDD890, was used to explore the metabolic reprogramming of two Mtb knockout mutants (pfkA- and icl-mutants), lacking key enzymes of central carbon metabolism, while exposed to changing nutritional conditions (oxygen, and carbon and nitrogen sources). A combination of shadow pricing, sensitivity analysis, and flux distributions patterns allowed us to identify metabolic behaviors that are in agreement with phenotypes reported in the literature. During hypoxia, at high glucose consumption, the Mtb pfkA-mutant showed a detrimental growth effect derived from the accumulation of toxic sugar phosphate intermediates (glucose-6-phosphate and fructose-6-phosphate) along with an increment of carbon fluxes towards the reductive direction of the tricarboxylic acid cycle (TCA). Furthermore, metabolic reprogramming of the icl-mutant (icl1&icl2) showed the importance of the methylmalonyl pathway for the detoxification of propionyl-CoA, during growth at high fatty acid consumption rates and aerobic conditions. At elevated levels of fatty acid uptake and hypoxia, we found a drop in TCA cycle intermediate accumulation that might create redox imbalance. Finally, findings regarding Mtb-mutant metabolic adaptation associated with asparagine consumption and acetate, succinate and alanine production, were in agreement with literature reports. This study demonstrates the potential application of genome-scale modeling, flux balance analysis (FBA), phenotypic phase plane (PhPP) analysis and shadow pricing to generate valuable insights about Mtb metabolic reprogramming in the context of human granulomas.

Incision of trivalent chromium [Cr(III)]-induced DNA damage by Bacillus caldotenax UvrABC endonuclease.

PubMed

O'Brien, Travis J; Jiang, Guohui; Chun, Gina; Mandel, H George; Westphal, Craig S; Kahen, Kaveh; Montaser, Akbar; States, J Christopher; Patierno, Steven R

2006-11-07

Some hexavalent chromium [Cr(VI)]-containing compounds are lung carcinogens. Once within cells, Cr(VI) is reduced to trivalent chromium [Cr(III)] which displays an affinity for both DNA bases and the phosphate backbone. A diverse array of genetic lesions is produced by Cr including Cr-DNA monoadducts, DNA interstrand crosslinks (ICLs), DNA-Cr-protein crosslinks (DPCs), abasic sites, DNA strand breaks and oxidized bases. Despite the large amount of information available on the genotoxicity of Cr, little is known regarding the molecular mechanisms involved in the removal of these lesions from damaged DNA. Recent work indicates that nucleotide excision repair (NER) is involved in the processing of Cr-DNA adducts in human and rodent cells. In order to better understand this process at the molecular level and begin to identify the Cr-DNA adducts processed by NER, the incision of CrCl(3) [Cr(III)]-damaged plasmid DNA was studied using a thermal-resistant UvrABC NER endonuclease from Bacillus caldotenax (Bca). Treatment of plasmid DNA with Cr(III) (as CrCl(3)) increased DNA binding as a function of dose. For example, at a Cr(III) concentration of 1 microM we observed approximately 2 Cr(III)-DNA adducts per plasmid. At this same concentration of Cr(III) we found that approximately 17% of the plasmid DNA contained ICLs ( approximately 0.2 ICLs/plasmid). When plasmid DNA treated with Cr(III) (1 microM) was incubated with Bca UvrABC we observed approximately 0.8 incisions/plasmid. The formation of endonuclease IV-sensitive abasic lesions or Fpg-sensitive oxidized DNA bases was not detected suggesting that the incision of Cr(III)-damaged plasmid DNA by UvrABC was not related to the generation of oxidized DNA damage. Taken together, our data suggest that a sub-fraction of Cr(III)-DNA adducts is recognized and processed by the prokaryotic NER machinery and that ICLs are not necessarily the sole lesions generated by Cr(III) that are substrates for NER.

AMP-activated protein kinase is involved in the activation of the Fanconi anemia/BRCA pathway in response to DNA interstrand crosslinks

PubMed Central

Hwang, Soo Kyung; Kim, Bong Sub; Kim, Hyoun Geun; Choi, Hae In; Kim, Jong Heon; Goh, Sung Ho; Lee, Chang-Hun

2016-01-01

Fanconi anemia complementation group (FANC) proteins constitute the Fanconi Anemia (FA)/BRCA pathway that is activated in response to DNA interstrand crosslinks (ICLs). We previously performed yeast two-hybrid screening to identify novel FANC-interacting proteins and discovered that the alpha subunit of AMP-activated protein kinase (AMPKα1) was a candidate binding partner of the FANCG protein, which is a component of the FA nuclear core complex. We confirmed the interaction between AMPKα and both FANCG using co-immunoprecipitation experiments. Additionally, we showed that AMPKα interacted with FANCA, another component of the FA nuclear core complex. AMPKα knockdown in U2OS cells decreased FANCD2 monoubiquitination and nuclear foci formation upon mitomycin C-induced ICLs. Furthermore, AMPKα knockdown enhanced cellular sensitivity to MMC. MMC treatment resulted in an increase in AMPKα phosphorylation/activation, indicating AMPK is involved in the cellular response to ICLs. FANCA was phosphorylated by AMPK at S347 and phosphorylation increased with MMC treatment. MMC-induced FANCD2 monoubiquitination and nuclear foci formation were compromised in a U2OS cell line that stably overexpressed the S347A mutant form of FANCA compared to wild-type FANCA-overexpressing cells, indicating a requirement for FANCA phosphorylation at S347 for proper activation of the FA/BRCA pathway. Our data suggest AMPK is involved in the activation of the FA/BRCA pathway. PMID:27449087

Conformational Profiling of the AT1 Angiotensin II Receptor Reflects Biased Agonism, G Protein Coupling, and Cellular Context.

PubMed

Devost, Dominic; Sleno, Rory; Pétrin, Darlaine; Zhang, Alice; Shinjo, Yuji; Okde, Rakan; Aoki, Junken; Inoue, Asuka; Hébert, Terence E

2017-03-31

Here, we report the design and use of G protein-coupled receptor-based biosensors to monitor ligand-mediated conformational changes in receptors in intact cells. These biosensors use bioluminescence resonance energy transfer with Renilla luciferase (RlucII) as an energy donor, placed at the distal end of the receptor C-tail, and the small fluorescent molecule FlAsH as an energy acceptor, its binding site inserted at different positions throughout the intracellular loops and C-terminal tail of the angiotensin II type I receptor. We verified that the modifications did not compromise receptor localization or function before proceeding further. Our biosensors were able to capture effects of both canonical and biased ligands, even to the extent of discriminating between different biased ligands. Using a combination of G protein inhibitors and HEK 293 cell lines that were CRISPR/Cas9-engineered to delete Gα q , Gα 11 , Gα 12 , and Gα 13 or β-arrestins, we showed that Gα q and Gα 11 are required for functional responses in conformational sensors in ICL3 but not ICL2. Loss of β-arrestin did not alter biased ligand effects on ICL2P2. We also demonstrate that such biosensors are portable between different cell types and yield context-dependent readouts of G protein-coupled receptor conformation. Our study provides mechanistic insights into signaling events that depend on either G proteins or β-arrestin. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

OPTICAL COLORS OF INTRACLUSTER LIGHT IN THE VIRGO CLUSTER CORE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rudick, Craig S.; Mihos, J. Christopher; Harding, Paul

2010-09-01

We continue our deep optical imaging survey of the Virgo cluster using the CWRU Burrell Schmidt telescope by presenting B-band surface photometry of the core of the Virgo cluster in order to study the cluster's intracluster light (ICL). We find ICL features down to {mu}{sub B} {approx}29 mag arcsec{sup -2}, confirming the results of Mihos et al., who saw a vast web of low surface brightness streams, arcs, plumes, and diffuse light in the Virgo cluster core using V-band imaging. By combining these two data sets, we are able to measure the optical colors of many of the cluster's lowmore » surface brightness features. While much of our imaging area is contaminated by galactic cirrus, the cluster core near the cD galaxy, M87, is unobscured. We trace the color profile of M87 out to over 2000'', and find a blueing trend with radius, continuing out to the largest radii. Moreover, we have measured the colors of several ICL features which extend beyond M87's outermost reaches and find that they have similar colors to the M87's halo itself, B - V {approx}0.8. The common colors of these features suggest that the extended outer envelopes of cD galaxies, such as M87, may be formed from similar streams, created by tidal interactions within the cluster, that have since dissolved into a smooth background in the cluster potential.« less

Machine learning for epigenetics and future medical applications

PubMed Central

Holder, Lawrence B.; Haque, M. Muksitul; Skinner, Michael K.

2017-01-01

ABSTRACT Understanding epigenetic processes holds immense promise for medical applications. Advances in Machine Learning (ML) are critical to realize this promise. Previous studies used epigenetic data sets associated with the germline transmission of epigenetic transgenerational inheritance of disease and novel ML approaches to predict genome-wide locations of critical epimutations. A combination of Active Learning (ACL) and Imbalanced Class Learning (ICL) was used to address past problems with ML to develop a more efficient feature selection process and address the imbalance problem in all genomic data sets. The power of this novel ML approach and our ability to predict epigenetic phenomena and associated disease is suggested. The current approach requires extensive computation of features over the genome. A promising new approach is to introduce Deep Learning (DL) for the generation and simultaneous computation of novel genomic features tuned to the classification task. This approach can be used with any genomic or biological data set applied to medicine. The application of molecular epigenetic data in advanced machine learning analysis to medicine is the focus of this review. PMID:28524769

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Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-09

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Towards a Molecular Understanding of the Fanconi Anemia Core Complex

PubMed Central

Hodson, Charlotte; Walden, Helen

2012-01-01

Fanconi Anemia (FA) is a genetic disorder characterized by the inability of patient cells to repair DNA damage caused by interstrand crosslinking agents. There are currently 14 verified FA genes, where mutation of any single gene prevents repair of DNA interstrand crosslinks (ICLs). The accumulation of ICL damage results in genome instability and patients having a high predisposition to cancers. The key event of the FA pathway is dependent on an eight-protein core complex (CC), required for the monoubiquitination of each member of the FANCD2-FANCI complex. Interestingly, the majority of patient mutations reside in the CC. The molecular mechanisms underlying the requirement for such a large complex to carry out a monoubiquitination event remain a mystery. This paper documents the extensive efforts of researchers so far to understand the molecular roles of the CC proteins with regard to its main function in the FA pathway, the monoubiquitination of FANCD2 and FANCI. PMID:22675617

Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Joo, Woo; Xu, Guozhou; Persky, Nicole S.

2011-08-29

Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each proteinmore » has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.« less

Structure of the FANCI-FANCD2 Complex: Insights into the Fanconi Anemia DNA Repair Pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

W Joo; G Xu; n Persky

2011-12-31

Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the {approx}300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each proteinmore » has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.« less

ICL-based TDLAS sensor for real-time breath gas analysis of carbon monoxide isotopes.

PubMed

Ghorbani, Ramin; Schmidt, Florian M

2017-05-29

We present a compact sensor for carbon monoxide (CO) in air and exhaled breath based on a room temperature interband cascade laser (ICL) operating at 4.69 µm, a low-volume circular multipass cell and wavelength modulation absorption spectroscopy. A fringe-limited (1σ) sensitivity of 6.5 × 10 -8 cm -1 Hz -1/2 and a detection limit of 9 ± 5 ppbv at 0.07 s acquisition time are achieved, which constitutes a 25-fold improvement compared to direct absorption spectroscopy. Integration over 10 s increases the precision to 0.6 ppbv. The setup also allows measuring the stable isotope 13 CO in breath. We demonstrate quantification of indoor air CO and real-time detection of CO expirograms from healthy non-smokers and a healthy smoker before and after smoking. Isotope ratio analysis indicates depletion of 13 CO in breath compared to natural abundance.

Compact CH 4 sensor system based on a continuous-wave, low power consumption, room temperature interband cascade laser

DOE PAGES

Dong, Lei; Li, Chunguang; Sanchez, Nancy P.; ...

2016-01-05

A tunable diode laser absorption spectroscopy-based methane sensor, employing a dense-pattern multi-pass gas cell and a 3.3 µm, CW, DFB, room temperature interband cascade laser (ICL), is reported. The optical integration based on an advanced folded optical path design and an efficient ICL control system with appropriate electrical power management resulted in a CH 4 sensor with a small footprint (32 x 20 x 17 cm 3) and low-power consumption (6 W). Polynomial and least-squares fit algorithms are employed to remove the baseline of the spectral scan and retrieve CH 4 concentrations, respectively. An Allan-Werle deviation analysis shows that themore » measurement precision can reach 1.4 ppb for a 60 s averaging time. Continuous measurements covering a seven-day period were performed to demonstrate the stability and robustness of the reported CH 4 sensor system.« less

Interband cascade lasers with >40% continuous-wave wallplug efficiency at cryogenic temperatures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Canedy, C. L.; Kim, C. S.; Merritt, C. D.

2015-09-21

Broad-area 10-stage interband cascade lasers (ICLs) emitting at λ = 3.0–3.2 μm are shown to maintain continuous-wave (cw) wallplug efficiencies exceeding 40% at temperatures up to 125 K, despite having a design optimized for operation at ambient and above. The cw threshold current density at 80 K is only 11 A/cm{sup 2} for a 2 mm cavity with anti-reflection/high-reflection coatings on the two facets. The external differential quantum efficiency for a 1-mm-long cavity with the same coatings is 70% per stage at 80 K, and still above 65% at 150 K. The results demonstrate that at cryogenic temperatures, where free carrier absorption losses are minimized, ICLs can convert electricalmore » to optical energy nearly as efficiently as the best specially designed intersubband-based quantum cascade lasers.« less

InAs-based interband-cascade-lasers emitting around 7 μm with threshold current densities below 1 kA/cm{sup 2} at room temperature

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dallner, Matthias; Hau, Florian; Kamp, Martin

2015-01-26

Interband cascade lasers (ICLs) grown on InAs substrates with threshold current densities below 1 kA/cm{sup 2} are presented. Two cascade designs with different lengths of the electron injector were investigated. Using a cascade design with 3 InAs quantum wells (QWs) in the electron injector, a device incorporating 22 stages in the active region exhibited a threshold current density of 940 A/cm{sup 2} at a record wavelength of 7 μm for ICLs operating in pulsed mode at room temperature. By investigating the influence of the number of stages on the device performance for a cascade design with 2 QWs in the electron injector, amore » further reduction of the threshold current density to 800 A/cm{sup 2} was achieved for a 30 stage device.« less

Compact CH 4 sensor system based on a continuous-wave, low power consumption, room temperature interband cascade laser

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Lei; Li, Chunguang; Sanchez, Nancy P.

A tunable diode laser absorption spectroscopy-based methane sensor, employing a dense-pattern multi-pass gas cell and a 3.3 µm, CW, DFB, room temperature interband cascade laser (ICL), is reported. The optical integration based on an advanced folded optical path design and an efficient ICL control system with appropriate electrical power management resulted in a CH 4 sensor with a small footprint (32 x 20 x 17 cm 3) and low-power consumption (6 W). Polynomial and least-squares fit algorithms are employed to remove the baseline of the spectral scan and retrieve CH 4 concentrations, respectively. An Allan-Werle deviation analysis shows that themore » measurement precision can reach 1.4 ppb for a 60 s averaging time. Continuous measurements covering a seven-day period were performed to demonstrate the stability and robustness of the reported CH 4 sensor system.« less

The HST Frontier Field MACS 1159.5+2223: Flanking Observations for Intracluster Light

NASA Astrophysics Data System (ADS)

Gonzalez, Anthony

2017-08-01

We propose a 6 orbit WFC3/IR imaging program targeting the environs of the HST Frontier Field cluster MACS 1149.5+2223 to obtain a comprehensive view of the intracluster stellar population in a massive galaxy cluster. WFC3/IR enables a vast improvement over ground-based studies in mapping emission from diffuse stellar populations. Our proposed observations are designed to build upon the existing investment in the Frontier Fields to conduct a new, more complete census of the intracluster light (ICL) extending out to 750 kpc. The requested observations are constructed to span the gap between the primary and parallel HFF pointings, detecting ICL to a surface brightness of 29.5 mag per square arcsec in F160W (equivalent to 31.5 mag per square arcsec in V-band). This depth is sufficient to trace the radial ICL profile out to 750 kpc from the BCG. These data will also yield a high-fidelity calibration of the background sky level, enabling two-dimensional mapping of the distribution and color of intracluster light down to 27 mag per square arcsec in F160W. From these maps we will quantify spatial variation in the ratio of the stellar baryons to the ICM, establishing whether the observed low scatter in the global ratio masks underlying smaller scale inhomogeneities due to astrophysical processes in the cluster. The requested observations further serve as a pilot program, enabling future similar analyses with the full ensemble of HFF clusters, and developing techniques that will be required for such low surface brightness programs with upcoming facilities including Euclid and WFIRST.

Defects in the Fanconi Anemia Pathway and Chromatid Cohesion in Head and Neck Cancer.

PubMed

Stoepker, Chantal; Ameziane, Najim; van der Lelij, Petra; Kooi, Irsan E; Oostra, Anneke B; Rooimans, Martin A; van Mil, Saskia E; Brink, Arjen; Dietrich, Ralf; Balk, Jesper A; Ylstra, Bauke; Joenje, Hans; Feller, Stephan M; Brakenhoff, Ruud H

2015-09-01

Failure to repair DNA damage or defective sister chromatid cohesion, a process essential for correct chromosome segregation, can be causative of chromosomal instability (CIN), which is a hallmark of many types of cancers. We investigated how frequent this occurs in head and neck squamous cell carcinoma (HNSCC) and whether specific mechanisms or genes could be linked to these phenotypes. The genomic instability syndrome Fanconi anemia is caused by mutations in any of at least 16 genes regulating DNA interstrand crosslink (ICL) repair. Since patients with Fanconi anemia have a high risk to develop HNSCC, we investigated whether and to which extent Fanconi anemia pathway inactivation underlies CIN in HNSCC of non-Fanconi anemia individuals. We observed ICL-induced chromosomal breakage in 9 of 17 (53%) HNSCC cell lines derived from patients without Fanconi anemia. In addition, defective sister chromatid cohesion was observed in five HNSCC cell lines. Inactivation of FANCM was responsible for chromosomal breakage in one cell line, whereas in two other cell lines, somatic mutations in PDS5A or STAG2 resulted in inadequate sister chromatid cohesion. In addition, FANCF methylation was found in one cell line by screening an additional panel of 39 HNSCC cell lines. Our data demonstrate that CIN in terms of ICL-induced chromosomal breakage and defective chromatid cohesion is frequently observed in HNSCC. Inactivation of known Fanconi anemia and chromatid cohesion genes does explain CIN in the minority of cases. These findings point to phenotypes that may be highly relevant in treatment response of HNSCC. ©2015 American Association for Cancer Research.

Crystal structure of a Fanconi anemia-associated nuclease homolog bound to 5' flap DNA: basis of interstrand cross-link repair by FAN1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gwon, Gwang Hyeon; Kim, Youngran; Liu, Yaqi

2014-10-15

Fanconi anemia (FA) is an autosomal recessive genetic disorder caused by defects in any of 15 FA genes responsible for processing DNA interstrand cross-links (ICLs). The ultimate outcome of the FA pathway is resolution of cross-links, which requires structure-selective nucleases. FA-associated nuclease 1 (FAN1) is believed to be recruited to lesions by a monoubiquitinated FANCI–FANCD2 (ID) complex and participates in ICL repair. Here, we determined the crystal structure of Pseudomonas aeruginosa FAN1 (PaFAN1) lacking the UBZ (ubiquitin-binding zinc) domain in complex with 5' flap DNA. All four domains of the right-hand-shaped PaFAN1 are involved in DNA recognition, with each domainmore » playing a specific role in bending DNA at the nick. The six-helix bundle that binds the junction connects to the catalytic viral replication and repair (VRR) nuclease (VRR nuc) domain, enabling FAN1 to incise the scissile phosphate a few bases distant from the junction. The six-helix bundle also inhibits the cleavage of intact Holliday junctions. PaFAN1 shares several conserved features with other flap structure-selective nucleases despite structural differences. A clamping motion of the domains around the wedge helix, which acts as a pivot, facilitates nucleolytic cleavage. The PaFAN1 structure provides insights into how archaeal Holliday junction resolvases evolved to incise 5' flap substrates and how FAN1 integrates with the FA complex to participate in ICL repair.« less

Mid-infrared dual-gas sensor for simultaneous detection of methane and ethane using a single continuous-wave interband cascade laser

DOE PAGES

Ye, Weilin; Li, Chunguang; Zheng, Chuantao; ...

2016-07-18

A continuous-wave (CW) interband cascade laser (ICL) based mid-infrared sensor system was demonstrated for simultaneous detection of atmospheric methane (CH 4) and ethane (C 2H 6). A 3.337 µm CW ICL with an emitting wavenumber range of 2996.0–3001.5 cm –1 was used to simultaneously target two absorption lines, C 2H 6 at 2996.88 cm –1 and CH 4 at 2999.06 cm –1, respectively. The sensor performance was first evaluated for single-gas detection by only targeting the absorption line of one gas species. Allan deviations of 11.2 parts per billion in volume (ppbv) for CH 4 and 1.86 ppbv for Cmore » 2H 6 with an averaging time of 3.4 s were achieved for the detection of these two gases. Dual-gas detection was realized by using a long-term scan signal to target both CH 4 and C 2H 6 lines. The Allan deviations increased slightly to 17.4 ppbv for CH 4 and 2.4 ppbv for C 2H 6 with an averaging time of 4.6 s due to laser temperature and power drift caused by long-term wavelength scanning. Measurements for both indoor and outdoor concentration changes of CH 4 and C 2H 6 were conducted. As a result, the reported single ICL based dual-gas sensor system has the advantages of reduced size and cost compared to two separate sensor systems.« less

Mid-infrared dual-gas sensor for simultaneous detection of methane and ethane using a single continuous-wave interband cascade laser

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye, Weilin; Li, Chunguang; Zheng, Chuantao

A continuous-wave (CW) interband cascade laser (ICL) based mid-infrared sensor system was demonstrated for simultaneous detection of atmospheric methane (CH 4) and ethane (C 2H 6). A 3.337 µm CW ICL with an emitting wavenumber range of 2996.0–3001.5 cm –1 was used to simultaneously target two absorption lines, C 2H 6 at 2996.88 cm –1 and CH 4 at 2999.06 cm –1, respectively. The sensor performance was first evaluated for single-gas detection by only targeting the absorption line of one gas species. Allan deviations of 11.2 parts per billion in volume (ppbv) for CH 4 and 1.86 ppbv for Cmore » 2H 6 with an averaging time of 3.4 s were achieved for the detection of these two gases. Dual-gas detection was realized by using a long-term scan signal to target both CH 4 and C 2H 6 lines. The Allan deviations increased slightly to 17.4 ppbv for CH 4 and 2.4 ppbv for C 2H 6 with an averaging time of 4.6 s due to laser temperature and power drift caused by long-term wavelength scanning. Measurements for both indoor and outdoor concentration changes of CH 4 and C 2H 6 were conducted. As a result, the reported single ICL based dual-gas sensor system has the advantages of reduced size and cost compared to two separate sensor systems.« less

Characterization of the human SNM1A and SNM1B/Apollo DNA repair exonucleases.

PubMed

Sengerová, Blanka; Allerston, Charles K; Abu, Mika; Lee, Sook Y; Hartley, Janet; Kiakos, Konstantinos; Schofield, Christopher J; Hartley, John A; Gileadi, Opher; McHugh, Peter J

2012-07-27

Human SNM1A and SNM1B/Apollo have both been implicated in the repair of DNA interstrand cross-links (ICLs) by cellular studies, and SNM1B is also required for telomere protection. Here, we describe studies on the biochemical characterization of the SNM1A and SNM1B proteins. The results reveal some fundamental differences in the mechanisms of the two proteins. Both SNM1A and SNM1B digest double-stranded and single-stranded DNA with a 5'-to-3' directionality in a reaction that is stimulated by divalent cations, and both nucleases are inhibited by the zinc chelator o-phenanthroline. We find that SNM1A has greater affinity for single-stranded DNA over double-stranded DNA that is not observed with SNM1B. Although both proteins demonstrate a low level of processivity on low molecular weight DNA oligonucleotide substrates, when presented with high molecular weight DNA, SNM1A alone is rendered much more active, being capable of digesting kilobase-long stretches of DNA. Both proteins can digest past ICLs induced by the non-distorting minor groove cross-linking agent SJG-136, albeit with SNM1A showing a greater capacity to achieve this. This is consistent with the proposal that SNM1A and SNM1B might exhibit some redundancy in ICL repair. Together, our work establishes differences in the substrate selectivities of SNM1A and SNM1B that are likely to be relevant to their in vivo roles and which might be exploited in the development of selective inhibitors.

Lamin A/C Depletion Enhances DNA Damage-Induced Stalled Replication Fork Arrest

PubMed Central

Singh, Mayank; Hunt, Clayton R.; Pandita, Raj K.; Kumar, Rakesh; Yang, Chin-Rang; Horikoshi, Nobuo; Bachoo, Robert; Serag, Sara; Story, Michael D.; Shay, Jerry W.; Powell, Simon N.; Gupta, Arun; Jeffery, Jessie; Pandita, Shruti; Chen, Benjamin P. C.; Deckbar, Dorothee; Löbrich, Markus; Yang, Qin; Khanna, Kum Kum; Worman, Howard J.

2013-01-01

The human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in LMNA result in altered nuclear morphology, but how this impacts the mechanisms that maintain genomic stability is unclear. Here, we report that lamin A/C-deficient cells have a normal response to ionizing radiation but are sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with ICL agents (cisplatin, camptothecin, and mitomycin), lamin A/C-deficient cells displayed normal γ-H2AX focus formation but a higher frequency of cells with delayed γ-H2AX removal, decreased recruitment of the FANCD2 repair factor, and a higher frequency of chromosome aberrations. Similarly, following hydroxyurea-induced replication stress, lamin A/C-deficient cells had an increased frequency of cells with delayed disappearance of γ-H2AX foci and defective repair factor recruitment (Mre11, CtIP, Rad51, RPA, and FANCD2). Replicative stress also resulted in a higher frequency of chromosomal aberrations as well as defective replication restart. Taken together, the data can be interpreted to suggest that lamin A/C has a role in the restart of stalled replication forks, a prerequisite for initiation of DNA damage repair by the homologous recombination pathway, which is intact in lamin A/C-deficient cells. We propose that lamin A/C is required for maintaining genomic stability following replication fork stalling, induced by either ICL damage or replicative stress, in order to facilitate fork regression prior to DNA damage repair. PMID:23319047

Surgical intervention and accommodative responses, I: centripetal ciliary body, capsule, and lens movements in rhesus monkeys of various ages.

PubMed

Croft, Mary Ann; McDonald, Jared P; James, Rebecca J; Heatley, Gregg A; Lin, Ting-Li; Lütjen-Drecoll, Elke; Kaufman, Paul L

2008-12-01

To determine how surgically altering the normal relationship between the lens and the ciliary body in rhesus monkeys affects centripetal ciliary body and lens movement. In 18 rhesus monkey eyes (aged 6-27 years), accommodation was induced before and after surgery by electrical stimulation of the Edinger-Westphal nucleus. Accommodative amplitude was measured by coincidence refractometry. Goniovideography was performed before and after intra- and extracapsular lens extraction (ICLE, ECLE) and anterior regional zonulolysis (ARZ). Centripetal lens/capsule movements, centripetal ciliary process (CP) movements, and circumlental space were measured by computerized image analysis of the goniovideography images. Centripetal accommodative CP and capsule movement increased in velocity and amplitude after, compared with before, ECLE regardless of age (n = 5). The presence of the lens substance retarded capsule movement by approximately 21% in the young eyes and by approximately 62% in the older eyes. Post-ICLE compared with pre-ICLE centripetal accommodative CP movement was dampened in all eyes in which the anterior vitreous was disrupted (n = 7), but not in eyes in which the anterior vitreous was left intact (n = 2). After anterior regional zonulolysis (n = 4), lens position shifted toward the lysed quadrant during accommodation. The presence of the lens substance, capsule zonular attachments, and Wieger's ligament may play a role in centripetal CP movement. The capsule is still capable of centripetal movement in the older eye (although at a reduced capacity) and may have the ability to produce approximately 6 D of accommodation in the presence of a normal, young crystalline lens or a similar surrogate.

Organic carbon dynamics and soil stability in five semiarid agroecosystems

USDA-ARS?s Scientific Manuscript database

In the semiarid Texas High Plains where continuous cotton (CTN) is the dominate cropping practice, alternative agroecosystems such as integrated crop-livestock agroecosystems (ICL) are gaining interest for their versatility in management approaches to conserve water in this water-limited environment...

40 CFR 82.8 - Grant of essential use allowances and critical use allowances.

Code of Federal Regulations, 2011 CFR

2011-07-01

...-IP America 250,516 19,576 TriCal, Inc 7,800 610 Total ** 1,814,020 141,755 * For production or import.... Degesch America, Inc. Helena Chemical Co. Hendrix & Dail Hy-Yield Products, LLC ICL-IP America Industrial...

40 CFR 82.8 - Grant of essential use allowances and critical use allowances.

Code of Federal Regulations, 2010 CFR

2010-07-01

...-IP America 250,516 19,576 TriCal, Inc 7,800 610 Total ** 1,814,020 141,755 * For production or import.... Degesch America, Inc. Helena Chemical Co. Hendrix & Dail Hy-Yield Products, LLC ICL-IP America Industrial...

Linking Soil Microbial Ecology to Ecosystem Functioning in Integrated Crop-Livestock Systems

USDA-ARS?s Scientific Manuscript database

Enhanced soil stability, nutrient cycling and C sequestration potential are important ecosystem functions driven by soil microbial processes and are directly influenced by agricultural management. Integrated crop-livestock agroecosystems (ICL) can enhance these functions via high-residue returning c...

Photo-Activated Psoralen Binds the ErbB2 Catalytic Kinase Domain, Blocking ErbB2 Signaling and Triggering Tumor Cell Apoptosis

PubMed Central

Xia, Wenle; Gooden, David; Liu, Leihua; Zhao, Sumin; Soderblom, Erik J.; Toone, Eric J.; Beyer, Wayne F.; Walder, Harold; Spector, Neil L.

2014-01-01

Photo-activation of psoralen with UVA irradiation, referred to as PUVA, is used in the treatment of proliferative skin disorders. The anti-proliferative effects of PUVA have been largely attributed to psoralen intercalation of DNA, which upon UV treatment, triggers the formation of interstrand DNA crosslinks (ICL) that inhibit transcription and DNA replication. Here, we show that PUVA exerts antitumor effects in models of human breast cancer that overexpress the ErbB2 receptor tyrosine kinase oncogene, through a new mechanism. Independent of ICL formation, the antitumor effects of PUVA in ErbB2+ breast cancer models can instead be mediated through inhibition of ErbB2 activation and signaling. Using a mass spectroscopy-based approach, we show for the first time that photo-activated 8MOP (8-methoxypsoralen) interacts with the ErbB2 catalytic autokinase domain. Furthermore, PUVA can reverse therapeutic resistance to lapatinib and other ErbB2 targeted therapies, including resistance mediated via expression of a phosphorylated, truncated form of ErbB2 (p85ErbB2) that is preferentially expressed in tumor cell nuclei. Current ErbB2 targeted therapies, small molecule kinase inhibitors or antibodies, do not block the phosphorylated, activated state of p85ErbB2. Here we show that PUVA reduced p85ErbB2 phosphorylation leading to tumor cell apoptosis. Thus, in addition to its effects on DNA and the formation of ICL, PUVA represents a novel ErbB2 targeted therapy for the treatment of ErbB2+ breast cancers, including those that have developed resistance to other ErbB2 targeted therapies. PMID:24551203

The Virgo cD galaxy M87 and its environment as mapped by Planetary Nebulae

NASA Astrophysics Data System (ADS)

Longobardi, Alessia

2015-08-01

Cosmological simulations predict the evolution of galaxy halos in cluster environments. Because of their low surface brightness, 1% of the night sky or lower, it is difficult to measure their spatial distribution and line-of-sight motions of the associated stars. Planetary nebulas (PNs) are very good tracers of their parent stellar populations, and we can use them to investigate these extended halos as consequence of their relatively strong [OIII] emission line. We have used PNs to study the outer halo of M87, the BCG at the center of the Virgo cluster. From the deepest and most extended narrow band survey done with Supruime Cam on Subaru, we carry out the spectroscopic follow up with FLMES at the VLT of more than 300 emission line objects in the halo of M87 out to ~150 kpc in radius. We confirm 254 PNs associated with the M87 halo and 44 with the intracluster light in the Virgo core. We show that the galaxy halo overlaps with the Virgo intracluster light (ICL) at all distance. Halo and ICL are dynamically distinct components, have different density profiles and parent stellar populations. The latter result shows that the halo of M87 is redder and more metal rich than the ICL population. Because of the excellent spectra resolution of our data, we identify a chevron structure in the projected phase space and identify the substructure in light associated to this dynamical sub-component. This accretion event account for a third of the light of the halo at 90 kpc distance from the center. It shows that at these distances the M87 halo is significantly lumpy and still growing by accretion of satellites.

Long-term control of CMV retinitis in a patient with idiopathic CD4+ T lymphocytopenia.

PubMed

Yashiro, Shigeko; Fujino, Yujiro; Tachikawa, Natsuo; Inamochi, Kazuya; Oka, Shinichi

2013-04-01

Cytomegalovirus (CMV) retinitis with idiopathic CD4(+) T lymphocytopenia (ICL) is rare and difficult to control. We report a first case for long-term control of CMV retinitis with ICL using interleukin-2 (IL-2) therapy and succeeded in discontinuation of anti-CMV therapy. A 49-year-old Japanese woman was diagnosed with ICL based on low CD4(+) count (72/μl), negative for HIV-1 and -2 antibodies, and absence of any defined immunodeficiency diseases or immunosuppressive therapy. PCR test of the aqueous humor in the right eye was suggestive of CMV retinitis. She was treated with systemic ganciclovir, but after several relapses of CMV retinitis, rhegmatogenous retinal detachment appeared in the right eye and she became blind in that eye. Three years later, she developed CMV retinitis in the left eye. Although she received systemic and focal anti-CMV treatments, the retinitis showed no improvement. Finally, retinal detachment occurred, and she underwent vitrectomy. IL-2 was injected to increase CD4(+) counts. Because of hyperpyrexia, blepharedema, central scotoma, and color anomaly, we changed to low-dose IL-2 therapy with no side effects. Finally, we succeeded in increasing the CD4(+) count to more than 200/μl after discontinuation of low-dose IL-2 therapy. CMV retinitis never recurred after discontinuation of anti-CMV therapy, with good visual acuity of 20/20 in the left eye. She developed blindness of the first affected right eye, whereas the visual acuity of the left eye remains excellent more than 12 years after the onset of CMV retinitis through the combined use of anti-CMV therapy, IL-2 therapy, and vitrectomy.

A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perez-Aguilar, Jose Manuel; Shan, Jufang; LeVine, Michael V.

With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT 2AR) in the absence of ligand and bound to four distinct serotonergic agonists. Themore » 5-HT 2AR is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT 2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT 2AR interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. Lastly, the findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT 2AR activation.« less

A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2

DOE PAGES

Perez-Aguilar, Jose Manuel; Shan, Jufang; LeVine, Michael V.; ...

2014-10-14

With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT 2AR) in the absence of ligand and bound to four distinct serotonergic agonists. Themore » 5-HT 2AR is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT 2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT 2AR interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. Lastly, the findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT 2AR activation.« less

Learning from a paradox: recent insights into Fanconi anaemia through studying mouse models.

PubMed

Bakker, Sietske T; de Winter, Johan P; te Riele, Hein

2013-01-01

Fanconi anaemia (FA) is a rare autosomal recessive or X-linked inherited disease characterised by an increased incidence of bone marrow failure (BMF), haematological malignancies and solid tumours. Cells from individuals with FA show a pronounced sensitivity to DNA interstrand crosslink (ICL)-inducing agents, which manifests as G2-M arrest, chromosomal aberrations and reduced cellular survival. To date, mutations in at least 15 different genes have been identified that cause FA; the products of all of these genes are thought to function together in the FA pathway, which is essential for ICL repair. Rapidly following the discovery of FA genes, mutant mice were generated to study the disease and the affected pathway. These mutant mice all show the characteristic cellular ICL-inducing agent sensitivity, but only partially recapitulate the developmental abnormalities, anaemia and cancer predisposition seen in individuals with FA. Therefore, the usefulness of modelling FA in mice has been questioned. In this Review, we argue that such scepticism is unjustified. We outline that haematopoietic defects and cancer predisposition are manifestations of FA gene defects in mice, albeit only in certain genetic backgrounds and under certain conditions. Most importantly, recent work has shown that developmental defects in FA mice also arise with concomitant inactivation of acetaldehyde metabolism, giving a strong clue about the nature of the endogenous lesion that must be repaired by the functional FA pathway. This body of work provides an excellent example of a paradox in FA research: that the dissimilarity, rather than the similarity, between mice and humans can provide insight into human disease. We expect that further study of mouse models of FA will help to uncover the mechanistic background of FA, ultimately leading to better treatment options for the disease.

Comparing pymorph and SDSS photometry - II. The differences are more than semantics and are not dominated by intracluster light

NASA Astrophysics Data System (ADS)

Bernardi, M.; Fischer, J.-L.; Sheth, R. K.; Meert, A.; Huertas-Company, M.; Shankar, F.; Vikram, V.

2017-07-01

The Sloan Digital Sky Survey (SDSS) pipeline photometry underestimates the brightnesses of the most luminous galaxies. This is mainly because (I) the SDSS overestimates the sky background, and (II) single-component or two-component Sérsic-based models better fit the surface brightness profile of galaxies, especially at high luminosities, than the de Vaucouleurs model used by the SDSS pipeline. We use the pymorph photometric reductions to isolate effect (II) and show that it is the same in the full sample as in small group environments, and for satellites in the most massive clusters as well. None of these are expected to be significantly affected by intracluster light (ICL). We only see an additional effect for centrals in the most massive haloes, but we argue that even this is not dominated by ICL. Hence, for the vast majority of galaxies, the differences between pymorph and SDSS pipeline photometry cannot be ascribed to the semantics of whether or not one includes the ICL when describing the stellar mass of massive galaxies. Rather, they likely reflect differences in star formation or assembly histories. Failure to account for the SDSS underestimate has significantly biased most previous estimates of the SDSS luminosity and stellar mass functions, and therefore halo model estimates of the z ˜ 0.1 relation between the mass of a halo and that of the galaxy at its centre. We also show that when one studies correlations, at fixed group mass, with a quantity that was not used to define the groups, then selection effects appear. We show why such effects arise and should not be mistaken for physical effects.

SURGICAL INTERVENTION AND ACCOMMODATIVE RESPONSES: I. CENTRIPETAL CILIARY BODY, CAPSULE AND LENS MOVEMENT IN RHESUS MONKEYS OF VARYING AGE

PubMed Central

Croft, Mary Ann; Mcdonald, Jared P.; James, Rebecca J.; Heatley, Gregg A.; Lin, Ting-Li; Lütjen-Drecoll, Elke; Kaufman, Paul L.

2009-01-01

Purpose To determine how surgically altering the normal relationship between the lens and the ciliary body in rhesus monkeys affects centripetal ciliary body and lens movement. Methods In 18 rhesus monkey eyes (aged 6–27 years), accommodation was induced before and after surgery by electrical stimulation of the Edinger-Westphal (E–W) nucleus. Accommodative amplitude was measured by coincidence refractometry. Goniovideography was performed before and after intra- and extra-capsular lens extraction (ICLE, ECLE) and anterior regional zonulolysis. Centripetal lens/capsule movements, centripetal ciliary process (CP) movements, and circumlental space were measured by computerized image analysis of the goniovideography images. Results Centripetal accommodative CP and capsule movement increased in velocity and amplitude post-ECLE compared to pre-ECLE regardless of age (n=5). The presence of the lens substance retarded capsule movement by ~21% in the young eyes and by ~62% in the older eyes. Post-ICLE compared to pre-ICLE centripetal accommodative CP movement was dampened in all eyes in which the anterior vitreous was disturbed (n=7), but not in eyes in which the anterior vitreous was left intact (n=2). Following anterior regional zonulolysis (n=4), lens position shifted toward the lysed quadrant during accommodation. Conclusions The presence of the lens substance, capsule zonular attachments, and Wiegers ligament may play a role in centripetal CP movement. The capsule is still capable of centripetal movement in the older eye (although at a reduced capacity) and may have the ability to produce ~6 diopters of accommodation in the presence of a normal young crystalline lens or a similar surrogate. PMID:18552393

MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor.

PubMed

Takahashi, Masanobu; Koi, Minoru; Balaguer, Francesc; Boland, C Richard; Goel, Ajay

2011-04-08

The MSH3 gene is one of the DNA mismatch repair (MMR) genes that has undergone somatic mutation frequently in MMR-deficient cancers. MSH3, together with MSH2, forms the MutSβ heteroduplex, which interacts with interstrand cross-links (ICLs) induced by drugs such as cisplatin and psoralen. However, the precise role of MSH3 in mediating the cytotoxic effects of ICL-inducing agents remains poorly understood. In this study, we first examined the effects of MSH3 deficiency on cytotoxicity caused by cisplatin and oxaliplatin, another ICL-inducing platinum drug. Using isogenic HCT116-derived clones in which MSH3 expression is controlled by shRNA expression in a Tet-off system, we discovered that MSH3 deficiency sensitized cells to both cisplatin and oxaliplatin at clinically relevant doses. Interestingly, siRNA-induced down-regulation of the MLH1 protein did not affect MSH3-dependent toxicity of these drugs, indicating that this process does not require participation of the canonical MMR pathway. Furthermore, MSH3-deficient cells maintained higher levels of phosphorylated histone H2AX and 53BP1 after oxaliplatin treatment in comparison with MSH3-proficient cells, suggesting that MSH3 plays an important role in repairing DNA double strand breaks (DSBs). This role of MSH3 was further supported by our findings that MSH3-deficient cells were sensitive to olaparib, a poly(ADP-ribose) polymerase inhibitor. Moreover, the combination of oxaliplatin and olaparib exhibited a synergistic effect compared with either treatment individually. Collectively, our results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair. These data lay the foundation for the development of effective prediction and treatments for cancers with MSH3 deficiency.

MSH3 Mediates Sensitization of Colorectal Cancer Cells to Cisplatin, Oxaliplatin, and a Poly(ADP-ribose) Polymerase Inhibitor*

PubMed Central

Takahashi, Masanobu; Koi, Minoru; Balaguer, Francesc; Boland, C. Richard; Goel, Ajay

2011-01-01

The MSH3 gene is one of the DNA mismatch repair (MMR) genes that has undergone somatic mutation frequently in MMR-deficient cancers. MSH3, together with MSH2, forms the MutSβ heteroduplex, which interacts with interstrand cross-links (ICLs) induced by drugs such as cisplatin and psoralen. However, the precise role of MSH3 in mediating the cytotoxic effects of ICL-inducing agents remains poorly understood. In this study, we first examined the effects of MSH3 deficiency on cytotoxicity caused by cisplatin and oxaliplatin, another ICL-inducing platinum drug. Using isogenic HCT116-derived clones in which MSH3 expression is controlled by shRNA expression in a Tet-off system, we discovered that MSH3 deficiency sensitized cells to both cisplatin and oxaliplatin at clinically relevant doses. Interestingly, siRNA-induced down-regulation of the MLH1 protein did not affect MSH3-dependent toxicity of these drugs, indicating that this process does not require participation of the canonical MMR pathway. Furthermore, MSH3-deficient cells maintained higher levels of phosphorylated histone H2AX and 53BP1 after oxaliplatin treatment in comparison with MSH3-proficient cells, suggesting that MSH3 plays an important role in repairing DNA double strand breaks (DSBs). This role of MSH3 was further supported by our findings that MSH3-deficient cells were sensitive to olaparib, a poly(ADP-ribose) polymerase inhibitor. Moreover, the combination of oxaliplatin and olaparib exhibited a synergistic effect compared with either treatment individually. Collectively, our results provide novel evidence that MSH3 deficiency contributes to the cytotoxicity of platinum drugs through deficient DSB repair. These data lay the foundation for the development of effective prediction and treatments for cancers with MSH3 deficiency. PMID:21285347

Mid-infrared dual-gas sensor for simultaneous detection of methane and ethane using a single continuous-wave interband cascade laser.

PubMed

Ye, Weilin; Li, Chunguang; Zheng, Chuantao; Sanchez, Nancy P; Gluszek, Aleksander K; Hudzikowski, Arkadiusz J; Dong, Lei; Griffin, Robert J; Tittel, Frank K

2016-07-25

A continuous-wave (CW) interband cascade laser (ICL) based mid-infrared sensor system was demonstrated for simultaneous detection of atmospheric methane (CH₄) and ethane (C₂H₆). A 3.337 µm CW ICL with an emitting wavenumber range of 2996.0-3001.5 cm^-1 was used to simultaneously target two absorption lines, C₂H₆ at 2996.88 cm^-1 and CH₄ at 2999.06 cm^-1, respectively. The sensor performance was first evaluated for single-gas detection by only targeting the absorption line of one gas species. Allan deviations of 11.2 parts per billion in volume (ppbv) for CH₄ and 1.86 ppbv for C₂H₆ with an averaging time of 3.4 s were achieved for the detection of these two gases. Dual-gas detection was realized by using a long-term scan signal to target both CH₄ and C₂H₆ lines. The Allan deviations increased slightly to 17.4 ppbv for CH₄ and 2.4 ppbv for C₂H₆ with an averaging time of 4.6 s due to laser temperature and power drift caused by long-term wavelength scanning. Measurements for both indoor and outdoor concentration changes of CH₄ and C₂H₆ were conducted. The reported single ICL based dual-gas sensor system has the advantages of reduced size and cost compared to two separate sensor systems.

Characterization of the Human SNM1A and SNM1B/Apollo DNA Repair Exonucleases*

PubMed Central

Sengerová, Blanka; Allerston, Charles K.; Abu, Mika; Lee, Sook Y.; Hartley, Janet; Kiakos, Konstantinos; Schofield, Christopher J.; Hartley, John A.; Gileadi, Opher; McHugh, Peter J.

2012-01-01

Human SNM1A and SNM1B/Apollo have both been implicated in the repair of DNA interstrand cross-links (ICLs) by cellular studies, and SNM1B is also required for telomere protection. Here, we describe studies on the biochemical characterization of the SNM1A and SNM1B proteins. The results reveal some fundamental differences in the mechanisms of the two proteins. Both SNM1A and SNM1B digest double-stranded and single-stranded DNA with a 5′-to-3′ directionality in a reaction that is stimulated by divalent cations, and both nucleases are inhibited by the zinc chelator o-phenanthroline. We find that SNM1A has greater affinity for single-stranded DNA over double-stranded DNA that is not observed with SNM1B. Although both proteins demonstrate a low level of processivity on low molecular weight DNA oligonucleotide substrates, when presented with high molecular weight DNA, SNM1A alone is rendered much more active, being capable of digesting kilobase-long stretches of DNA. Both proteins can digest past ICLs induced by the non-distorting minor groove cross-linking agent SJG-136, albeit with SNM1A showing a greater capacity to achieve this. This is consistent with the proposal that SNM1A and SNM1B might exhibit some redundancy in ICL repair. Together, our work establishes differences in the substrate selectivities of SNM1A and SNM1B that are likely to be relevant to their in vivo roles and which might be exploited in the development of selective inhibitors. PMID:22692201

The Phosphatidylinositol 3,5-Bisphosphate (PI(3,5)P2)-dependent Tup1 Conversion (PIPTC) Regulates Metabolic Reprogramming from Glycolysis to Gluconeogenesis*

PubMed Central

Han, Bong-Kwan; Emr, Scott D.

2013-01-01

Glucose/carbon metabolism is a fundamental cellular process in living cells. In response to varying environments, eukaryotic cells reprogram their glucose/carbon metabolism between aerobic or anaerobic glycolysis, oxidative phosphorylation, and/or gluconeogenesis. The distinct type of glucose/carbon metabolism that a cell carries out has significant effects on the cell's proliferation and differentiation. However, it is poorly understood how the reprogramming of glucose/carbon metabolism is regulated. Here, we report a novel endosomal PI(3,5)P2 lipid-dependent regulatory mechanism that is required for metabolic reprogramming from glycolysis to gluconeogenesis in Saccharomyces cerevisiae. Certain gluconeogenesis genes, such as FBP1 (encoding fructose-1,6-bisphosphatase 1) and ICL1 (encoding isocitrate lyase 1) are under control of the Mig1 repressor and Cyc8-Tup1 corepressor complex. We previously identified the PI(3,5)P2-dependent Tup1 conversion (PIPTC), a mechanism to convert Cyc8-Tup1 corepressor to Cti6-Cyc8-Tup1 coactivator. We demonstrate that the PIPTC plays a critical role for transcriptional activation of FBP1 and ICL1. Furthermore, without the PIPTC, the Cat8 and Sip4 transcriptional activators cannot be efficiently recruited to the promoters of FBP1 and ICL1, suggesting a key role for the PIPTC in remodulating the chromatin architecture at the promoters. Our findings expand our understanding of the regulatory mechanisms for metabolic reprogramming in eukaryotes to include key regulation steps outside the nucleus. Given that Tup1 and the metabolic enzymes that control PI(3,5)P2 are highly conserved among eukaryotes, our findings may provide important insights toward understanding glucose/carbon metabolic reprogramming in other eukaryotes, including humans. PMID:23733183

The phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-dependent Tup1 conversion (PIPTC) regulates metabolic reprogramming from glycolysis to gluconeogenesis.

PubMed

Han, Bong-Kwan; Emr, Scott D

2013-07-12

Glucose/carbon metabolism is a fundamental cellular process in living cells. In response to varying environments, eukaryotic cells reprogram their glucose/carbon metabolism between aerobic or anaerobic glycolysis, oxidative phosphorylation, and/or gluconeogenesis. The distinct type of glucose/carbon metabolism that a cell carries out has significant effects on the cell's proliferation and differentiation. However, it is poorly understood how the reprogramming of glucose/carbon metabolism is regulated. Here, we report a novel endosomal PI(3,5)P2 lipid-dependent regulatory mechanism that is required for metabolic reprogramming from glycolysis to gluconeogenesis in Saccharomyces cerevisiae. Certain gluconeogenesis genes, such as FBP1 (encoding fructose-1,6-bisphosphatase 1) and ICL1 (encoding isocitrate lyase 1) are under control of the Mig1 repressor and Cyc8-Tup1 corepressor complex. We previously identified the PI(3,5)P2-dependent Tup1 conversion (PIPTC), a mechanism to convert Cyc8-Tup1 corepressor to Cti6-Cyc8-Tup1 coactivator. We demonstrate that the PIPTC plays a critical role for transcriptional activation of FBP1 and ICL1. Furthermore, without the PIPTC, the Cat8 and Sip4 transcriptional activators cannot be efficiently recruited to the promoters of FBP1 and ICL1, suggesting a key role for the PIPTC in remodulating the chromatin architecture at the promoters. Our findings expand our understanding of the regulatory mechanisms for metabolic reprogramming in eukaryotes to include key regulation steps outside the nucleus. Given that Tup1 and the metabolic enzymes that control PI(3,5)P2 are highly conserved among eukaryotes, our findings may provide important insights toward understanding glucose/carbon metabolic reprogramming in other eukaryotes, including humans.

Comparison of postoperative vault height predictability using white-to-white or sulcus diameter-based sizing for the visian implantable collamer lens.

PubMed

Reinstein, Dan Z; Lovisolo, Carlo F; Archer, Timothy J; Gobbe, Marine

2013-01-01

To compare vault height predictability of Implantable Collamer Lens (ICL; Staar Surgical) sizing using a sulcus diameter-based formula or the manufacturer-recommended white-to-white-based method. In 50 myopic eyes, ICL size was calculated using both a formula including sulcus diameter and the traditional formula based on white-to-white diameter. Sulcus diameter was measured using Artemis 2 very high-frequency (VHF) digital ultrasound (ArcScan Inc). Implantation was based on the sulcus diameter derived size. Actual postoperative vault height achieved was measured by VHF digital ultrasound scanning. Circle segment trigonometry was used to calculate the vault height that would have resulted had lens sizing been based on the white-to-white formula. The same lens size would have been used in 60% of eyes, a smaller lens would have been used in 34% of eyes and a larger lens in 6% of eyes had lens sizing been based on the white-to-white formula. Mean vault for eyes with lenses sized using the sulcus diameter formula was 0.37±0.16 mm (range: 0.08 to 0.92 mm), with 2% <0.09 mm, the recognized low-vault height for risk of cataract. Circle segment trigonometry predicted that the vault height would have been 0.24±0.28 mm (range: -0.31 to 0.92 mm), with 26% <0.09 mm had lens sizing been based on the white-to-white formula. Significantly better predictability of postoperative vault height was achieved by including sulcus diameter into the ICL sizing formula compared with using the traditional white-to-white-based formula. Copyright 2013, SLACK Incorporated.

Integrated Case Learning: Teaching Clinical Reasoning

ERIC Educational Resources Information Center

Radomski, Natalie; Russell, John

2010-01-01

Learning how to "think like doctors" can be difficult for undergraduate medical students in their early clinical years. Our model of collaborative Integrated Case Learning (ICL) and simulated clinical reasoning aims to address these issues. Taking a socio-cultural perspective, this study investigates the reflective learning interactions…

Continuous spectroscopic measurement of methane isotopes and ethane made on board an aircraft: instrument configuration and characterisation

NASA Astrophysics Data System (ADS)

Pitt, Joseph; Young, Stuart; Hopkins, James; Lee, James; Bauguitte, Stéphane; Dorsey, James; Allen, Grant; Gallagher, Martin; Yacovitch, Tara; Zahniser, Mark; Fisher, Rebecca; Lowry, Dave; Nisbet, Euan

2017-04-01

We describe the configuration of two commercially available absorption spectrometers for use on board the UK Facility for Airborne Atmospheric Research (FAAM) aircraft. A dual laser instrument has been used to make continuous measurements of the atmospheric 13CH4:12CH4 ratio and ethane mole fraction, using an interband cascade laser (ICL) and a recently developed type of diode laser respectively. Simultaneous measurements of atmospheric ethane have also been made using a single laser instrument employing an ICL, enabling instrument inter-comparison. Instrument performance is evaluated over a series of test flights, and initial results from the MOYA (Methane Observations and Yearly Assessments) campaign, targeting biomass burning plumes in west Africa, are also presented. We describe the calibration procedure and data analysis approaches for methane isotope measurement, involving calibration over a range of methane isotopic composition and methane mole fraction. We assess the effectiveness of this calibration technique during the first MOYA campaign period using measurements of a target cylinder of known composition.

Centrin diversity and basal body patterning across evolution: new insights from Paramecium

PubMed Central

Balavoine, Guillaume; Lemullois, Michel; Bouhouche, Khaled; Beisson, Janine; Koll, France

2017-01-01

ABSTRACT First discovered in unicellular eukaryotes, centrins play crucial roles in basal body duplication and anchoring mechanisms. While the evolutionary status of the founding members of the family, Centrin2/Vfl2 and Centrin3/cdc31 has long been investigated, the evolutionary origin of other members of the family has received less attention. Using a phylogeny of ciliate centrins, we identify two other centrin families, the ciliary centrins and the centrins present in the contractile filaments (ICL centrins). In this paper, we carry on the functional analysis of still not well-known centrins, the ICL1e subfamily identified in Paramecium, and show their requirement for correct basal body anchoring through interactions with Centrin2 and Centrin3. Using Paramecium as well as a eukaryote-wide sampling of centrins from completely sequenced genomes, we revisited the evolutionary story of centrins. Their phylogeny shows that the centrins associated with the ciliate contractile filaments are widespread in eukaryotic lineages and could be as ancient as Centrin2 and Centrin3. PMID:28432105

Structural insights into 5‧ flap DNA unwinding and incision by the human FAN1 dimer

NASA Astrophysics Data System (ADS)

Zhao, Qi; Xue, Xiaoyu; Longerich, Simonne; Sung, Patrick; Xiong, Yong

2014-12-01

Human FANCD2-associated nuclease 1 (FAN1) is a DNA structure-specific nuclease involved in the processing of DNA interstrand crosslinks (ICLs). FAN1 maintains genomic stability and prevents tissue decline in multiple organs, yet it confers ICL-induced anti-cancer drug resistance in several cancer subtypes. Here we report three crystal structures of human FAN1 in complex with a 5‧ flap DNA substrate, showing that two FAN1 molecules form a head-to-tail dimer to locate the lesion, orient the DNA and unwind a 5‧ flap for subsequent incision. Biochemical experiments further validate our model for FAN1 action, as structure-informed mutations that disrupt protein dimerization, substrate orientation or flap unwinding impair the structure-specific nuclease activity. Our work elucidates essential aspects of FAN1-DNA lesion recognition and a unique mechanism of incision. These structural insights shed light on the cellular mechanisms underlying organ degeneration protection and cancer drug resistance mediated by FAN1.

Thermal effects of an ICL-based mid-infrared CH 4 sensor within a wide atmospheric temperature range

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ye, Weilin; Zheng, Chuantao; Sanchez, Nancy P.

Here, thermal effects of an interband cascade laser (ICL) based mid-infrared methane (CH 4) sensor that uses long-path absorption spectroscopy were studied. The sensor performance in the laboratory at a constant temperature of ~ 25°C was measured for 5 hours and its Allan deviation was ~ 2 ppbv with a 1 s averaging time. A LabVIEW-based simulation program was developed to study thermal effects on infrared absorption and a temperature compensation technique was developed to control such effects. An environmental test chamber was employed to investigate thermal effects that occur in the sensor system with variation of the test chambermore » temperature between 10 and 30°C. The thermal response of the sensor in a laboratory setting was observed using a 2.1 ppm CH 4 standard gas sample. indoor/outdoor CH 4 measurements were conducted to evaluate the sensor performance within a wide atmospheric temperature range.« less

A mutation affecting carbon catabolite repression suppresses growth defects in pyruvate carboxylase mutants from Saccharomyces cerevisiae.

PubMed

Blázquez, M A; Gamo, F J; Gancedo, C

1995-12-18

Yeasts with disruptions in the genes PYC1 and PYC2 encoding the isoenzymes of pyruvate carboxylase cannot grow in a glucose-ammonium medium (Stucka et al. (1991) Mol. Gen. Genet. 229, 307-315). We have isolated a dominant mutation, BPC1-1, that allows growth in this medium of yeasts with interrupted PYC1 and PYC2 genes. The BPC1-1 mutation abolishes catabolite repression of a series of genes and allows expression of the enzymes of the glyoxylate cycle during growth in glucose. A functional glyoxylate cycle is necessary for suppression as a disruption of gene ICL1 encoding isocitrate lyase abolished the phenotypic effect of BPC1-1 on growth in glucose-ammonium. Concurrent expression from constitutive promoters of genes ICL1 and MLS1 (encoding malate synthase) also suppressed the growth phenotype of pyc1 pyc2 mutants. The mutation BPC1-1 is either allelic or closely linked to the mutation DGT1-1.

Thermal effects of an ICL-based mid-infrared CH4 sensor within a wide atmospheric temperature range

NASA Astrophysics Data System (ADS)

Ye, Weilin; Zheng, Chuantao; Sanchez, Nancy P.; Girija, Aswathy V.; He, Qixin; Zheng, Huadan; Griffin, Robert J.; Tittel, Frank K.

2018-03-01

The thermal effects of an interband cascade laser (ICL) based mid-infrared methane (CH4) sensor that uses long-path absorption spectroscopy were studied. The sensor performance in the laboratory at a constant temperature of ∼25 °C was measured for 5 h and its Allan deviation was ∼2 ppbv with a 1 s averaging time. A LabVIEW-based simulation program was developed to study thermal effects on infrared absorption and a temperature compensation technique was developed to minimize these effects. An environmental test chamber was employed to investigate the thermal effects that occur in the sensor system with variation of the test chamber temperature between 10 and 30 °C. The thermal response of the sensor in a laboratory setting was observed using a 2.1 ppm CH4 standard gas sample. Indoor/outdoor CH4 measurements were conducted to evaluate the sensor performance within a wide atmospheric temperature range.

Compact CH{sub 4} sensor system based on a continuous-wave, low power consumption, room temperature interband cascade laser

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Lei, E-mail: donglei@sxu.edu.cn; State Key Laboratory of Quantum Optics and Quantum Optics Devices, Institute of Laser Spectroscopy, Shanxi University, Taiyuan 030006; Li, Chunguang

A tunable diode laser absorption spectroscopy-based methane sensor, employing a dense-pattern multi-pass gas cell and a 3.3 μm, CW, DFB, room temperature interband cascade laser (ICL), is reported. The optical integration based on an advanced folded optical path design and an efficient ICL control system with appropriate electrical power management resulted in a CH{sub 4} sensor with a small footprint (32 × 20 × 17 cm{sup 3}) and low-power consumption (6 W). Polynomial and least-squares fit algorithms are employed to remove the baseline of the spectral scan and retrieve CH{sub 4} concentrations, respectively. An Allan-Werle deviation analysis shows that the measurement precision can reach 1.4 ppb for amore » 60 s averaging time. Continuous measurements covering a seven-day period were performed to demonstrate the stability and robustness of the reported CH{sub 4} sensor system.« less

DNA Damage Induced by Alkylating Agents and Repair Pathways

PubMed Central

Kondo, Natsuko; Takahashi, Akihisa; Ono, Koji; Ohnishi, Takeo

2010-01-01

The cytotoxic effects of alkylating agents are strongly attenuated by cellular DNA repair processes, necessitating a clear understanding of the repair mechanisms. Simple methylating agents form adducts at N- and O-atoms. N-methylations are removed by base excision repair, AlkB homologues, or nucleotide excision repair (NER). O6-methylguanine (MeG), which can eventually become cytotoxic and mutagenic, is repaired by O6-methylguanine-DNA methyltransferase, and O6MeG:T mispairs are recognized by the mismatch repair system (MMR). MMR cannot repair the O6MeG/T mispairs, which eventually lead to double-strand breaks. Bifunctional alkylating agents form interstrand cross-links (ICLs) which are more complex and highly cytotoxic. ICLs are repaired by complex of NER factors (e.g., endnuclease xeroderma pigmentosum complementation group F-excision repair cross-complementing rodent repair deficiency complementation group 1), Fanconi anemia repair, and homologous recombination. A detailed understanding of how cells cope with DNA damage caused by alkylating agents is therefore potentially useful in clinical medicine. PMID:21113301

Thermal effects of an ICL-based mid-infrared CH 4 sensor within a wide atmospheric temperature range

DOE PAGES

Ye, Weilin; Zheng, Chuantao; Sanchez, Nancy P.; ...

2018-01-31

Here, thermal effects of an interband cascade laser (ICL) based mid-infrared methane (CH 4) sensor that uses long-path absorption spectroscopy were studied. The sensor performance in the laboratory at a constant temperature of ~ 25°C was measured for 5 hours and its Allan deviation was ~ 2 ppbv with a 1 s averaging time. A LabVIEW-based simulation program was developed to study thermal effects on infrared absorption and a temperature compensation technique was developed to control such effects. An environmental test chamber was employed to investigate thermal effects that occur in the sensor system with variation of the test chambermore » temperature between 10 and 30°C. The thermal response of the sensor in a laboratory setting was observed using a 2.1 ppm CH 4 standard gas sample. indoor/outdoor CH 4 measurements were conducted to evaluate the sensor performance within a wide atmospheric temperature range.« less

76 FR 76619 - International Mail: New Prices and Fee Changes-Mailing Services

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-08

... POSTAL SERVICE 39 CFR Part 20 International Mail: New Prices and Fee Changes--Mailing Services... Individual Country Listings (ICLs) to reflect price adjustments for First-Class Mail International[supreg... mailing services price adjustments with the Postal Regulatory Commission (PRC), effective on January 22...

The Magic Background of Pearl Harbor. Volume 3. Appendix

DTIC Science & Technology

1977-01-01

diplomatic relations and the opening of a warfare of commerce destruc- tion. C a JITSU TO Trans. 1-30-45 No. 406 Washington (Nomura) Tokyo September...icles.) Part 2. 2.Inthesummeroflastyear,FUJI-Elect!i,corderedfromSIEMENSfor(? JU ?)use10 automatic pilot compasses and JINKOSHIKOKra. However, exchange

78 FR 79446 - Notice of Public Information Collection(s) Being Reviewed by the Federal Communications...

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2013-12-30

... collection of information is necessary for the proper performance of the functions of the Commission... rate-of-return carriers (Interstate Common Line Support (ICLS)) to replace implicit support in interstate access charges with explicit support that is portable to all eligible telecommunications carriers...

Soil fungal community and fuctional diversity assessments of agroecosystems in the Southern High Plains

USDA-ARS?s Scientific Manuscript database

Soil fungi perform a variety of ecosystem functions that are crucial to maintaining agroecosystem sustainability including aggregate stability and soil carbon storage. The purpose of this study was to compare soil fungal communities and functional diversity in integrated crop and livestock (ICL) sy...

Supporting Effective Collaboration: Using a Rearview Mirror to Look Forward

ERIC Educational Resources Information Center

McManus, Margaret M.; Aiken, Robert M.

2016-01-01

Our original research, to design and develop an Intelligent Collaborative Learning System (ICLS), yielded the creation of a Group Leader Tutor software system which utilizes a Collaborative Skills Network to monitor students working collaboratively in a networked environment. The Collaborative Skills Network was a conceptualization of…

75 FR 81270 - Notice of Public Information Collection(s) Being Submitted for Review and Approval to the Office...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-27

... performance of the functions of the Commission, including whether the information shall have practical utility...-of-return carriers (Interstate Common Line Support (ICLS)) to replace implicit support in interstate access charges with explicit support that is portable to all eligible telecommunications carriers. The...

Idea-Centered Laboratory Science (I-CLS), [Unit] C, How a Scientist Expects His World To Behave.

ERIC Educational Resources Information Center

Van Deventer, William C.; Duyser, Lucille

The major ideas of this unit are: consistency and uniformity, cause and effect, and parsimony. Laboratory experiences consist of investigations into: projecting expectations, moon and stars, the relationships among different kinds of change (daily, monthly, annual temperature changes), force and motion, chemical reactions, superstitions, origin of…

Interferon Inducers against Infectious Diseases

DTIC Science & Technology

1990-07-13

22 7. Induction of IFN in Micoe by IC-(PLL- monosaccharides ............................... *23 8. ICL- CDS04...seeking to replace both PLL and CM by modifying the PLL with engrafted polysaccharides . 2. Background A number of candidates have been developed in this...expanders, or being closely related to such. These include gelatin, anionically-modified gelatin, oarboxymethyl polysaocharides, sulfated polysaccharides

Ppbv-Level Ethane Detection Using Quartz-Enhanced Photoacoustic Spectroscopy with a Continuous-Wave, Room Temperature Interband Cascade Laser

PubMed Central

Li, Chunguang; Dong, Lei; Zheng, Chuantao; Lin, Jun; Wang, Yiding

2018-01-01

A ppbv-level quartz-enhanced photoacoustic spectroscopy (QEPAS)-based ethane (C2H6) sensor was demonstrated by using a 3.3 μm continuous-wave (CW), distributed feedback (DFB) interband cascade laser (ICL). The ICL was employed for targeting a strong C2H6 absorption line located at 2996.88 cm−1 in its fundamental absorption band. Wavelength modulation spectroscopy (WMS) combined with the second harmonic (2f) detection technique was utilized to increase the signal-to-noise ratio (SNR) and simplify data acquisition and processing. Gas pressure and laser frequency modulation depth were optimized to be 100 Torr and 0.106 cm−1, respectively, for maximizing the 2f signal amplitude. Performance of the QEPAS sensor was evaluated using specially prepared C2H6 samples. A detection limit of 11 parts per billion in volume (ppbv) was obtained with a 1-s integration time based on an Allan-Werle variance analysis, and the detection precision can be further improved to ~1.5 ppbv by increasing the integration time up to 230 s. PMID:29495610

Metal-Diazo Radicals of α-Carbonyl Diazomethanes

PubMed Central

Li, Feifei; Xiao, Longqiang; Liu, Lijian

2016-01-01

Metal-diazo radicals of α-carbonyl diazomethanes are new members of the radical family and are precursors to metal-carbene radicals. Herein, using electron paramagnetic resonance spectroscopy with spin-trapping, we detect diazo radicals of α-carbonyl diazomethanes, induced by [RhICl(cod)]2, [CoII(por)] and PdCl2, at room temperature. The unique quintet signal of the Rh-diazo radical was observed in measurements of α-carbonyl diazomethane adducts of [RhICl(cod)]2 in the presence of 5,5-dimethyl-pyrroline-1-N-oxide (DMPO). DFT calculations indicated that 97.2% of spin density is localized on the diazo moiety. Co- and Pd-diazo radicals are EPR silent but were captured by DMPO to form spin adducts of DMPO-N∙ (triplet-of-sextets signal). The spin-trapping also provides a powerful tool for detection of metal-carbene radicals, as evidenced by the DMPO-trapped carbene radicals (DMPO-C∙, sextet signal) and 2-methyl-2-nitrosopropane-carbene adducts (MNP-C∙, doublet-of-triplets signal). The transformation of α-carbonyl diazomethanes to metal-carbene radicals was confirmed to be a two-step process via metal-diazo radicals. PMID:26960916

Metal-Diazo Radicals of α-Carbonyl Diazomethanes

NASA Astrophysics Data System (ADS)

Li, Feifei; Xiao, Longqiang; Liu, Lijian

2016-03-01

Metal-diazo radicals of α-carbonyl diazomethanes are new members of the radical family and are precursors to metal-carbene radicals. Herein, using electron paramagnetic resonance spectroscopy with spin-trapping, we detect diazo radicals of α-carbonyl diazomethanes, induced by [RhICl(cod)]2, [CoII(por)] and PdCl2, at room temperature. The unique quintet signal of the Rh-diazo radical was observed in measurements of α-carbonyl diazomethane adducts of [RhICl(cod)]2 in the presence of 5,5-dimethyl-pyrroline-1-N-oxide (DMPO). DFT calculations indicated that 97.2% of spin density is localized on the diazo moiety. Co- and Pd-diazo radicals are EPR silent but were captured by DMPO to form spin adducts of DMPO-N• (triplet-of-sextets signal). The spin-trapping also provides a powerful tool for detection of metal-carbene radicals, as evidenced by the DMPO-trapped carbene radicals (DMPO-C•, sextet signal) and 2-methyl-2-nitrosopropane-carbene adducts (MNP-C•, doublet-of-triplets signal). The transformation of α-carbonyl diazomethanes to metal-carbene radicals was confirmed to be a two-step process via metal-diazo radicals.

Research on propane leak detection system and device based on mid infrared laser

NASA Astrophysics Data System (ADS)

Jiang, Meng; Wang, Xuefeng; Wang, Junlong; Wang, Yizhao; Li, Pan; Feng, Qiaoling

2017-10-01

Propane is a key component of liquefied petroleum gas (LPG) and crude oil volatile. This issue summarizes the recent progress of propane detection technology. Meanwhile, base on the development trend, our latest progress is also provided. We demonstrated a mid infrared propane sensor system, which is based on wavelength modulation spectroscopy (WMS) technique with a CW interband cascade laser (ICL) emitting at 3370.4nm. The ICL laser scanned over a sharp feature in the broader spectrum of propane, and harmonic signals are obtained by lock-in amplifier for gas concentration deduction. The surrounding gas is extracted into the fine optical absorption cell through the pump to realize online detection. The absorption cell is designed in mid infrared windows range. An example experimental setup is shown. The second harmonic signals 2f and first harmonic signals1f are obtained. We present the sensor performance test data including dynamic precision and temperature stability. The propane detection sensor system and device is portable can carried on the mobile inspection vehicle platforms or intelligent robot inspection platform to realize the leakage monitoring of whole oil gas tank area.

Replication Protein A (RPA) deficiency activates the Fanconi anemia DNA repair pathway.

PubMed

Jang, Seok-Won; Jung, Jin Ki; Kim, Jung Min

2016-09-01

The Fanconi anemia (FA) pathway regulates DNA inter-strand crosslink (ICL) repair. Despite our greater understanding of the role of FA in ICL repair, its function in the preventing spontaneous genome instability is not well understood. Here, we show that depletion of replication protein A (RPA) activates the FA pathway. RPA1 deficiency increases chromatin recruitment of FA core complex, leading to FANCD2 monoubiquitination (FANCD2-Ub) and foci formation in the absence of DNA damaging agents. Importantly, ATR depletion, but not ATM, abolished RPA1 depletion-induced FANCD2-Ub, suggesting that ATR activation mediated FANCD2-Ub. Interestingly, we found that depletion of hSSB1/2-INTS3, a single-stranded DNA-binding protein complex, induces FANCD2-Ub, like RPA1 depletion. More interestingly, depletion of either RPA1 or INTS3 caused increased accumulation of DNA damage in FA pathway deficient cell lines. Taken together, these results indicate that RPA deficiency induces activation of the FA pathway in an ATR-dependent manner, which may play a role in the genome maintenance.

Crystal Structures of the β2-Adrenergic Receptor

NASA Astrophysics Data System (ADS)

Weis, William I.; Rosenbaum, Daniel M.; Rasmussen, Søren G. F.; Choi, Hee-Jung; Thian, Foon Sun; Kobilka, Tong Sun; Yao, Xiao-Jie; Day, Peter W.; Parnot, Charles; Fung, Juan J.; Ratnala, Venkata R. P.; Kobilka, Brian K.; Cherezov, Vadim; Hanson, Michael A.; Kuhn, Peter; Stevens, Raymond C.; Edwards, Patricia C.; Schertler, Gebhard F. X.; Burghammer, Manfred; Sanishvili, Ruslan; Fischetti, Robert F.; Masood, Asna; Rohrer, Daniel K.

G protein coupled receptors (GPCRs) constitute the largest family of membrane proteins in the human genome, and are responsible for the majority of signal transduction events involving hormones and neuro-transmitters across the cell membrane. GPCRs that bind to diffusible ligands have low natural abundance, are relatively unstable in detergents, and display basal G protein activation even in the absence of ligands. To overcome these problems two approaches were taken to obtain crystal structures of the β2-adrenergic receptor (β2AR), a well-characterized GPCR that binds cate-cholamine hormones. The receptor was bound to the partial inverse agonist carazolol and co-crystallized with a Fab made to a three-dimensional epitope formed by the third intracellular loop (ICL3), or by replacement of ICL3 with T4 lysozyme. Small crystals were obtained in lipid bicelles (β2AR-Fab) or lipidic cubic phase (β2AR-T4 lysozyme), and diffraction data were obtained using microfocus technology. The structures provide insights into the basal activity of the receptor, the structural features that enable binding of diffusible ligands, and the coupling between ligand binding and G-protein activation.

Co-inhibition of Pol η and ATR sensitizes cisplatin-resistant non-small cell lung cancer cells to cisplatin by impeding DNA damage repair.

PubMed

Li, Xiao-Qin; Ren, Jin; Chen, Ping; Chen, Yu-Jiao; Wu, Min; Wu, Yan; Chen, Kang; Li, Jian

2018-05-31

For the majority of patients with advanced non-small cell lung cancer (NSCLC), the standard of care remains platinum-based chemotherapy. However, cisplatin resistance is a big obstacle to the treatment, and elucidation of its mechanism is warranted. In this study, we showed that there was no difference in intracellular uptake of cisplatin or the removal of platinum-DNA adducts between a cisplatin-resistant NSCLC cell line (A549/DR) and a cisplatin-sensitive NSCLC cell line (A549). However, the capacity to repair DNA interstrand crosslinks (ICLs) and double-strand breaks (DSBs) was significantly enhanced in the A549/DR cell line compared to 3 cisplatin-sensitive cell lines. We found that the protein and mRNA expression levels of Pol η, a Y-family translesion synthesis (TLS) polymerase, were markedly increased upon cisplatin exposure in A549/DR cells compared with A549 cells. Furthermore, intracellular co-localization of Pol η and proliferation cell nuclear antigen (PCNA) induced by cisplatin or cisplatin plus gemcitabine treatment was inhibited by depleting ataxia telangiectasia mutated and Rad-3-related (ATR). Pol η depletion by siRNA sensitized A549/DR cells to cisplatin; co-depletion of Pol η and ATR further increased A549/DR cell death induced by cisplatin or cisplatin plus gemcitabine compared to depletion of Pol η or ATR alone, concomitant with inhibition of DNA ICL and DSB repair and accumulation of DNA damage. No additional sensitization effect of co-depleting Pol η and ATR was observed in A549 cells. These results demonstrate that co-inhibition of Pol η and ATR reverses the drug resistance of cisplatin-resistant NSCLC cells by blocking the repair of DNA ICLs and DSBs induced by cisplatin or cisplatin plus gemcitabine.

Development of a coupled diffusion denuder system combined with gas chromatography/mass spectrometry for the separation and quantification of molecular iodine and the activated iodine compounds iodine monochloride and hypoiodous acid in the marine atmosphere.

PubMed

Huang, Ru-Jin; Hoffmann, Thorsten

2009-03-01

This study concerns the development of a coupled diffusion denuder system capable of separating and quantifying gaseous molecular iodine (I(2)) and two other highly reactive iodine species, ICl and HOI, which are collectively named activated iodine compounds (AIC). Both I(2) and AIC are key species in the atmospheric chemistry of iodine. 1,3,5-Trimethoxybenzene (1,3,5-TMB)- and alpha-cyclodextrin/(129)I(-) (alpha-CD/(129)I(-))-coated denuders proved to be suitable for the collection of gaseous AIC and I(2), respectively. The experimental collection efficiencies for AIC (tested as ICl) and I(2) agreed well with the theoretical values for gas flow rates in the range between 300 and 1800 mL min(-1). The coupled denuder system (1,3,5-TMB-coated denuder as front-denuder coupled upstream of an alpha-CD/(129)I(-)-coated denuder) was applied successfully to separate test gas mixtures of ICl and I(2) at various mixing ratios in the laboratory. The operation of both denuder systems was demonstrated to be independent of relative humidity (0-100%) and storage period (at least 2 weeks prior to and after sampling). Detection limits were achieved at sub-parts-per-trillion-by-volume (sub-pptv) level. The presented method provides a reliable and practical approach for the speciation of gaseous iodine compounds. In addition, we report for the first time ambient air measurements of AIC mixing ratios, carried out at the atmospheric research station in Mace Head, Ireland. A maximum concentration of AIC of 30.2 pptv was observed for nighttime measurements and 6.0 pptv for daytime measurements. A similar diurnal pattern was found for I(2) with an average concentration level of 23.2 pptv during daytime and 85.1 pptv during nighttime, indicating a strong correlation with AIC.

77 FR 14297 - Connect America Fund; a National Broadband Plan for Our Future; Establishing Just and Reasonable...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... Reduction Act requirements, and finds good cause to delete certain rules that are now obsolete. DATES... Paperwork Reduction Act (PRA) requirements, and finds good cause to delete certain rules that are now... CAF phase I support,'' but excludes Interstate Common Line Support (ICLS) on the basis that it...

A Multi-Metric Assessment on the Impact of I Can Learn[R] (ICL) Multimedia on Actual and Perceived Student Achievement in Developmental Mathematics

ERIC Educational Resources Information Center

Stokes, Sandra D.

2011-01-01

This quasi-experimental study focused on the initiatives undertaken by a community college's Academic Skills Enhancement Program (ASEP) commonly known as the Developmental Education Department to find an alternative delivery method to aid its students in learning developmental mathematics. Moreover, this study (1) conducted a comparative…

75 FR 29555 - Medicare Program; Medicare Coverage Gap Discount Program Model Manufacturer Agreement and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-26

... Center Hotel, 101 West Fayette Street, Baltimore, MD 21201. Registration and Special Accommodations... percent of the Part D negotiated price for covered Part D claims above the ICL until their TrOOP costs... of an amount equal to the negotiated price (as defined in section 1860D- 14A(g)(6) of the Act...

Plasma Theory and Simulation.

DTIC Science & Technology

1978-07-01

l l) A paper t i t led “Part icle-Fluid Hybrid Codes Applied to Beam- Plasma , Ring -Plasma Instabi l i ties ” was presented at Monterey (see Section V...ic le-Fluid Hybr id Codes Applied to Beam- Plasma , Ring -Plasma Ins tab i l i t ies”. (2) A. Peiravi and C. K. Birdsall , “Self-Heating of id Therma l

Procurement and Delivery of Joint Service Armor Protected Vehicles

DTIC Science & Technology

2009-01-29

veh icle mi x of MRAPs and UA II and their rcspecti ve cfl ’ccts on opcrationaltactics, technique , Md procedurcs, as we ll as vehic le forma ti ons...rcasonablc price compari sons with prior purchases orthe same 01’ similar items made on a competiti ve bas is 0 1’ supported by va lid cost 0 1’ Iri

Interferon Inducers Against Infectious Diseases.

DTIC Science & Technology

1991-06-15

mouse there was little, if any, difference. b. PLL- Monosaccharide Grafts. The PLL-dextran grafts described above contain long polysaccharide chains...engrafted polysaccharides . Our research has resulted in the demonstration that effective IFN inducers can be formulated without using...Action of IC-(PLL-dextran) .............. 7. Induction of IFN in Mice by IC-(PLL- monosaccharides ). I 8. ICL-SCDS04; Compositions and IFN Titers

Non-covalent Interactions with SUMO and Ubiquitin Orchestrate Distinct Functions of the SLX4 Complex in Genome Maintenance

PubMed Central

Ouyang, Jian; Garner, Elizabeth; Hallet, Alexander; Nguyen, Hai Dang; Rickman, Kimberly A.; Gill, Grace; Smogorzewska, Agata; Zou, Lee

2014-01-01

SLX4, a coordinator of multiple DNA structure-specific endonucleases, is important for several DNA repair pathways. Non-covalent interactions of SLX4 with ubiquitin are required for localizing SLX4 to DNA-interstrand crosslinks (ICLs), yet how SLX4 is targeted to other functional contexts remains unclear. Here, we show that SLX4 binds SUMO-2/3 chains via SUMO-interacting motifs (SIMs). The SIMs of SLX4 are dispensable for ICL repair, but important for processing CPT-induced replication intermediates, suppressing fragile site instability, and localizing SLX4 to ALT telomeres. The localization of SLX4 to laser-induced DNA damage also requires the SIMs, as well as DNA-end resection, UBC9 and MDC1. Furthermore, the SUMO binding of SLX4 enhances its interaction with specific DNA-damage sensors or telomere-binding proteins, including RPA, MRE11-RAD50-NBS1 and TRF2. Thus, the interactions of SLX4 with SUMO and ubiquitin increase its affinity for factors recognizing different DNA lesions or telomeres, helping to direct the SLX4 complex in distinct functional contexts. PMID:25533185

Coexistence of two electronic nano-phases on a CH 3NH 3PbI 3–xCl x surface observed in STM measurements

DOE PAGES

Yost, Andrew J.; Pimachev, Artem; Ho, Chun -Chih; ...

2016-10-10

Scanning tunneling microscopy is utilized to investigate the local density of states of a CH 3NH 3PbI 3-xCl x perovskite in cross-sectional geometry. Two electronic phases, 10-20 nm in size, with different electronic properties inside the CH 3NH 3PbI 3-xCl x perovskite layer are observed by the dI/ dV mapping and point spectra. A power law dependence of the dI/dV point spectra is revealed. In addition, the distinct electronic phases are found to have preferential orientations close to the normal direction of the film surface. Density functional theory calculations indicate that the observed electronic phases are associated with local deviationmore » of I/Cl ratio, rather than different orientations of the electric dipole moments in the ferroelectric phases. Furthermore, by comparing the calculated results with experimental data we conclude that phase A (lower contrast in dI/dV mapping at -2.0 V bias) contains a lower I/Cl ratio than that in phase B (higher contrast in dI/dV).« less

Crosslinking reactions of 4-amino-6-oxo-2-vinylpyrimidine with guanine derivatives and structural analysis of the adducts

PubMed Central

Kusano, Shuhei; Ishiyama, Shogo; Lam, Sik Lok; Mashima, Tsukasa; Katahira, Masato; Miyamoto, Kengo; Aida, Misako; Nagatsugi, Fumi

2015-01-01

DNA interstrand crosslinks (ICLs) are the primary mechanism for the cytotoxic activity of many clinical anticancer drugs, and numerous strategies for forming ICLs have been developed. One such method is using crosslink-forming oligonucleotides (CFOs). In this study, we designed a 4-amino-6-oxo-2-vinylpyrimidine (AOVP) derivative with an acyclic spacer to react selectively with guanine. The AOVP CFO exhibited selective crosslinking reactivity with guanine and thymine in DNA, and with guanine in RNA. These crosslinking reactions with guanine were accelerated in the presence of CoCl2, NiCl2, ZnCl2 and MnCl2. In addition, we demonstrated that the AOVP CFO was reactive toward 8-oxoguanine opposite AOVP in the duplex DNA. The structural analysis of each guanine and 8-oxoguanine adduct in the duplex DNA was investigated by high-resolution NMR. The results suggested that AOVP reacts at the N2 amine in guanine and at the N1 or N2 amines in 8-oxoguanine in the duplex DNA. This study demonstrated the first direct determination of the adduct structure in duplex DNA without enzyme digestion. PMID:26245348

Hybrid tandem quantum dot/organic photovoltaic cells with complementary near infrared absorption

NASA Astrophysics Data System (ADS)

Kim, Taesoo; Palmiano, Elenita; Liang, Ru-Ze; Hu, Hanlin; Murali, Banavoth; Kirmani, Ahmad R.; Firdaus, Yuliar; Gao, Yangqin; Sheikh, Arif; Yuan, Mingjian; Mohammed, Omar F.; Hoogland, Sjoerd; Beaujuge, Pierre M.; Sargent, Edward H.; Amassian, Aram

2017-05-01

Monolithically integrated hybrid tandem solar cells that effectively combine solution-processed colloidal quantum dot (CQD) and organic bulk heterojunction subcells to achieve tandem performance that surpasses the individual subcell efficiencies have not been demonstrated to date. In this work, we demonstrate hybrid tandem cells with a low bandgap PbS CQD subcell harvesting the visible and near-infrared photons and a polymer:fullerene—poly (diketopyrrolopyrrole-terthiophene) (PDPP3T):[6,6]-phenyl-C60-butyric acid methyl ester (PC61BM)—top cell absorbing effectively the red and near-infrared photons of the solar spectrum in a complementary fashion. The two subcells are connected in series via an interconnecting layer (ICL) composed of a metal oxide layer, a conjugated polyelectrolyte, and an ultrathin layer of Au. The ultrathin layer of Au forms nano-islands in the ICL, reducing the series resistance, increasing the shunt resistance, and enhancing the device fill-factor. The hybrid tandems reach a power conversion efficiency (PCE) of 7.9%, significantly higher than the PCE of the corresponding individual single cells, representing one of the highest efficiencies reported to date for hybrid tandem solar cells based on CQD and polymer subcells.

Usefulness of acr expression for monitoring latent Mycobacterium tuberculosis bacilli in 'in vitro' and 'in vivo' experimental models.

PubMed

Gordillo, S; Guirado, E; Gil, O; Díaz, J; Amat, I; Molinos, S; Vilaplana, C; Ausina, V; Cardona, P-J

2006-07-01

Real-time RT-PCR was used to quantify the expression of genes possibly involved in Mycobacterium tuberculosis latency in in vitro and murine models. Exponential and stationary phase (EP and SP) bacilli were exposed to decreasing pH levels (from 6.5 to 4.5) in an unstirred culture, and mRNA levels for 16S rRNA, sigma factors sigA,B,E,F,G,H and M, Rv0834c, icl, nirA, narG, fpbB, acr, rpoA, recA and cysH were quantified. The expression of acr was the one that best correlated with the CFU decrease observed in SP bacilli. In the murine model, the expressions of icl, acr and sigF tended to decrease when bacillary counts increased and vice versa. Values from immunodepressed mice (e.g. alpha/beta T cells, TNF, IFN-gamma and iNOs knock out strains), with accelerated bacillary growth rate, confirmed this fact. Finally, the expression of acr was maintained in mice following long-term treatment with antibiotics. The quantification of acr expression could be useful for monitoring the presence of latent bacilli in some murine models of tuberculosis.

Discriminant WSRC for Large-Scale Plant Species Recognition.

PubMed

Zhang, Shanwen; Zhang, Chuanlei; Zhu, Yihai; You, Zhuhong

2017-01-01

In sparse representation based classification (SRC) and weighted SRC (WSRC), it is time-consuming to solve the global sparse representation problem. A discriminant WSRC (DWSRC) is proposed for large-scale plant species recognition, including two stages. Firstly, several subdictionaries are constructed by dividing the dataset into several similar classes, and a subdictionary is chosen by the maximum similarity between the test sample and the typical sample of each similar class. Secondly, the weighted sparse representation of the test image is calculated with respect to the chosen subdictionary, and then the leaf category is assigned through the minimum reconstruction error. Different from the traditional SRC and its improved approaches, we sparsely represent the test sample on a subdictionary whose base elements are the training samples of the selected similar class, instead of using the generic overcomplete dictionary on the entire training samples. Thus, the complexity to solving the sparse representation problem is reduced. Moreover, DWSRC is adapted to newly added leaf species without rebuilding the dictionary. Experimental results on the ICL plant leaf database show that the method has low computational complexity and high recognition rate and can be clearly interpreted.

Warrant Officer Examinations. PR-4018

DTIC Science & Technology

1944-10-10

ccouunting, Administrative - Clcorica1, Judge, Advo Ge~nc. De~ptsAdxiiniistrati~ve 1 icl Adi isrtv - Supp:ly, generaile8 ~ Administrativo ’ - Supply, Air...chronological index if action in processing special and summary records of trial. Answers teleph.’nic inquirie’s pertaining to subject matter contain- ed...reproduction by lithopraphy, black and white process printing, and gelatin duplication; moy couidinnte and supervise procurement, storage, and distribution of

Funding Higher Education and Wage Uncertainty: Income Contingent Loan versus Mortgage Loan

ERIC Educational Resources Information Center

Migali, Giuseppe

2012-01-01

We propose a simple theoretical model which shows how the combined effect of wage uncertainty and risk aversion can modify the individual willingness to pay for a HE system financed by an ICL or a ML. We calibrate our model using real data from the 1970 British Cohort Survey together with the features of the English HE financing system. We allow…

Project Management of Army Aircraft Survivability Equipment

DTIC Science & Technology

1976-11-01

develop- ment trade-offs; and request for proposal (RFP) reviews involving advanced development (AD), engineering development (ED), and pro- ducibility...Safety: Ensur~e that adequate consideration is given safetyf throughout the life cycle of aviation surviva- bility equipment. -13. Project Manager Training...rate management effort to assure an orderly progression through its life cyIcle. Many of the items carry an urgent priority for worldwide applicatic

RegA Plays a Key Role in Oxygen-Dependent Establishment of Persistence and in Isocitrate Lyase Activity, a Critical Determinant of In vivo Brucella suis Pathogenicity

PubMed Central

Abdou, Elias; Jiménez de Bagüés, María P.; Martínez-Abadía, Ignacio; Ouahrani-Bettache, Safia; Pantesco, Véronique; Occhialini, Alessandra; Al Dahouk, Sascha; Köhler, Stephan; Jubier-Maurin, Véronique

2017-01-01

For aerobic human pathogens, adaptation to hypoxia is a critical factor for the establishment of persistent infections, as oxygen availability is low inside the host. The two-component system RegB/A of Brucella suis plays a central role in the control of respiratory systems adapted to oxygen deficiency, and in persistence in vivo. Using an original “in vitro model of persistence” consisting in gradual oxygen depletion, we compared transcriptomes and proteomes of wild-type and ΔregA strains to identify the RegA-regulon potentially involved in the set-up of persistence. Consecutive to oxygen consumption resulting in growth arrest, 12% of the genes in B. suis were potentially controlled directly or indirectly by RegA, among which numerous transcriptional regulators were up-regulated. In contrast, genes or proteins involved in envelope biogenesis and in cellular division were repressed, suggesting a possible role for RegA in the set-up of a non-proliferative persistence state. Importantly, the greatest number of the RegA-repressed genes and proteins, including aceA encoding the functional IsoCitrate Lyase (ICL), were involved in energy production. A potential consequence of this RegA impact may be the slowing-down of the central metabolism as B. suis progressively enters into persistence. Moreover, ICL is an essential determinant of pathogenesis and long-term interactions with the host, as demonstrated by the strict dependence of B. suis on ICL activity for multiplication and persistence during in vivo infection. RegA regulates gene or protein expression of all functional groups, which is why RegA is a key regulator of B. suis in adaptation to oxygen depletion. This function may contribute to the constraint of bacterial growth, typical of chronic infection. Oxygen-dependent activation of two-component systems that control persistence regulons, shared by several aerobic human pathogens, has not been studied in Brucella sp. before. This work therefore contributes significantly to the unraveling of persistence mechanisms in this important zoonotic pathogen. PMID:28573107

Linking precious metal enrichment and halogen cycling in mafic magmatic systems: insights from the Rum layered intrusion, NW Scotland

NASA Astrophysics Data System (ADS)

Kelly, A. P.; O'Driscoll, B.; Clay, P. L.; Burgess, R.

2017-12-01

Layered intrusions host the world's largest known concentrations of the platinum-group elements (PGE). Emphasis has been attached to the role of halogen-bearing fluids in concentrating the precious metals, but whether this occurs at the magmatic stage, or via subsequent metasomatism, is actively debated. One obstacle to progress has been the analytical difficulty of measuring low abundances of the halogens in the cumulate products of layered intrusions. To elucidate the importance of the halogens in facilitating PGE-mineralisation, as well as fingerprint halogen provenance and assess the importance of halogen cycling in mafic magma systems more generally, a suite of samples encompassing different stages of activity of the Palaeogene Rum layered intrusion was investigated. Halogen abundances were measured by neutron irradiation noble gas mass spectrometric analysis, permitting the detection of relatively low (ppm-ppb) abundances of Cl, Br and I in mg-sized samples. The samples include PGE-enriched chromite seams, various cumulates (e.g., peridotites), picrites (approximating the Rum parental magma), and pegmatites representing volatile-rich melts that circulated the intrusion at a late-stage in its solidification history. The new data reveal that PGE-bearing chromite seams contain relatively low Cl concentrations (2-3 ppm), with high molar ratios of Br/Cl and I/Cl (0.005 and 0.009, respectively). The picrites and cumulates have Br/Cl and I/Cl ratios close to sub-continental lithospheric mantle values of approximately 0.0013 and 0.00002, respectively, and thus likely reflect the Rum magma source region. A positive correlation between Cl and Br signifies comparable partitioning behaviour in all samples. However, I is more variable, displaying a positive correlation with Cl for more primitive samples (e.g. picrite and peridotite), and seemingly decoupling from Br and Cl in chromite seams and pegmatites. The relative enrichment of I over Cl in the chromite seams points to the local involvement of an organic-rich sedimentary assimilant and potentially represents an important trigger for PGE-mineralisation. Similarly high I/Cl signatures in some of the late-stage pegmatites suggest that fluids with this distinctive composition circulated the cooling Rum intrusion for a protracted period of time.

Investigating the structural impact of S311C mutation in DRD2 receptor by molecular dynamics & docking studies.

PubMed

Podder, Avijit; Pandey, Deeksha; Latha, N

2016-04-01

Dopamine receptors (DR) are neuronal cell surface proteins that mediate the action of neurotransmitter dopamine in brain. Dopamine receptor D2 (DRD2) that belongs to G-protein coupled receptors (GPCR) family is a major therapeutic target for of various neurological and psychiatric disorders in human. The third inter cellular loop (ICL3) in DRD2 is essential for coupling G proteins and several signaling scaffold proteins. A mutation in ICL3 can interfere with this binding interface, thereby altering the DRD2 signaling. In this study we have examined the deleterious effect of serine to cysteine mutation at position 311 (S311C) in the ICL3 region that is implicated in diseases like schizophrenia and alcoholism. An in silico structure modeling approach was employed to determine the wild type (WT) and mutant S311C structures of DRD2, scaffold proteins - Gαi/o and NEB2. Protein-ligand docking protocol was exercised to predict the interactions of natural agonist dopamine with both the WT and mutant structures of DRD2. Besides, atomistic molecular dynamics (MD) simulations were performed to provide insights into essential dynamics of the systems-unbound and dopamine bound DRD2 (WT and mutant) and three independent simulations for Gαi, Gαo and NEB2 systems. To provide information on intra-molecular arrangement of the structures, a comprehensive residue interactions network of both dopamine bound WT and mutant DRD2 protein were studied. We also employed a protein-protein docking strategy to find the interactions of scaffold proteins - Gαi/o and NEB2 with both dopamine bound WT and mutant structures of DRD2. We observed a marginal effect of the mutation in dopamine binding mechanism on the trajectories analyzed. However, we noticed a significant structural alteration of the mutant receptor which affects Gαi/o and NEB2 binding that can be causal for malfunctioning in cAMP-dependent signaling and Ca(+) homeostasis in the brain dopaminergic system leading to neuropsychiatric disorders. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Assessment of normal perisellar anatomy in 1.5 T T2-weighted MRI and comparison with the anatomic criteria defining cavernous sinus invasion of pituitary adenomas.

PubMed

Knappe, U J; Jaursch-Hancke, C; Schönmayr, R; Lörcher, U

2009-08-01

The study aimed to evaluate the anatomical relations of sellar and perisellar structures with T2-weighted MRI and to apply criteria for cavernous sinus (CS) invasion by pituitary adenomas to normal sellar anatomy. Thin slice (3 mm) coronal T2-weighted MR-images (1.5 Tesla) were obtained in 117 individuals (234 CS) without pituitary disorders (58 females, 59 males; age 17 months to 87 years). In 99 cases data indicating the presence of arterial hypertension (AH) were available, 25 with AH, 74 without AH. The medial wall of the cavernous sinus was detectable in 33% of cases. The inferior rim of the horizontal part of the ICA was located at the level of the sellar floor in 33%, below in 47%, and above in 20%. The mean distance between the both ICAs was 17.8 mm (range, 7-38 mm). The mean distance between the pituitary and the ICA in AH was significantly shorter than in patients without AH (Chi-square, p=0.01). There was contact between the gland and the ICA in 41.5% of the cases. In 16.7% (39 sides) of all 234 SCs investigated, the area of contact between the ICA and the gland was at least 25% of the vessel's circumference. The medial intercarotid line (ICL) was crossed by the pituitary gland in 9% (21 of 234 CS), the central ICL was touched in another 5% (11 of 234 CS), lateral ICL was never reached. There was a weak correlation with age: a more extensive lateral extension of the gland was seen in individuals older than 40 years compared to younger individuals (Chi-square, p=0.03). There was a marked difference in the anatomical findings between both sides in 41.9% of cases. Inter- and intra-individual variations of the perisellar anatomy and its relation to the pituitary gland exist, which are partly related to age and AH. This must be remembered when the invasiveness of pituitary adenomas is assessed in MRI. Georg Thieme Verlag KG Stuttgart New York.

Room Temperature Interband Cascade Lasers

DTIC Science & Technology

2010-01-01

interband cascade laser (ICL) [6]-[8] is particularly convenient, since the semimetallic band alignment between InAs and GaSb allows the electrons that...superlattice claddings and a non-ohmic part that may be associated with various band discontinuities in the structure . While the latter can probably be...made a radiative transition to the valence band to be transferred readily back to the conduction band via elastic or nearly elastic processes. Our

Carbon Black - Polyethylene Composites for PTC (Positive Temperature Coefficient) Thermistor Applications

DTIC Science & Technology

1987-12-01

triphasic composite. Addition of the third filler yielded two effects. First, the filler provided sufficient mechanical stabilization of the composite...2000C. The stabilization was accomplished without diminishing the magnitude of the PTC effect. The triphasic composites also displayed equivalent or...differences in conductor and insulator --.-+icle size lead to the formation of quasi-compo- -s, resulting in a 3(0-3)-0 connectivity. Triphasic composites

Exjade® (deferasirox, ICL670) in the treatment of chronic iron overload associated with blood transfusion

PubMed Central

Cappellini, Maria Domenica

2007-01-01

Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. Although the current reference standard iron chelator deferoxamine has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Deferasirox (Exjade®, ICL670, Novartis Pharma AG, Basel, Switzerland) is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in adult and pediatric patients. The efficacy and safety of deferasirox have been established in a comprehensive clinical development program involving patients with various transfusion-dependent anemias. Deferasirox has a dose-dependent effect on iron burden, and is as efficacious as deferoxamine at comparable therapeutic doses. Deferasirox therapy can be tailored to a patient’s needs, as response is related to both dose and iron intake. Since deferasirox has a long half-life and is present in the plasma for 24 hours with once-daily dosing, it is unique in providing constant chelation coverage with a single dose. The availability of this convenient, effective, and well tolerated therapy represents a significant advance in the management of transfusional iron overload. PMID:18360637

Interband cascade laser based mid-infrared methane sensor system using a novel electrical-domain self-adaptive direct laser absorption spectroscopy (SA-DLAS).

PubMed

Song, Fang; Zheng, Chuantao; Yan, Wanhong; Ye, Weilin; Wang, Yiding; Tittel, Frank K

2017-12-11

To suppress sensor noise with unknown statistical properties, a novel self-adaptive direct laser absorption spectroscopy (SA-DLAS) technique was proposed by incorporating a recursive, least square (RLS) self-adaptive denoising (SAD) algorithm and a 3291 nm interband cascade laser (ICL) for methane (CH 4 ) detection. Background noise was suppressed by introducing an electrical-domain noise-channel and an expectation-known-based RLS SAD algorithm. Numerical simulations and measurements were carried out to validate the function of the SA-DLAS technique by imposing low-frequency, high-frequency, White-Gaussian and hybrid noise on the ICL scan signal. Sensor calibration, stability test and dynamic response measurement were performed for the SA-DLAS sensor using standard or diluted CH 4 samples. With the intrinsic sensor noise considered only, an Allan deviation of ~43.9 ppbv with a ~6 s averaging time was obtained and it was further decreased to 6.3 ppbv with a ~240 s averaging time, through the use of self-adaptive filtering (SAF). The reported SA-DLAS technique shows enhanced sensitivity compared to a DLAS sensor using a traditional sensing architecture and filtering method. Indoor and outdoor atmospheric CH 4 measurements were conducted to validate the normal operation of the reported SA-DLAS technique.

Selective dry etching of III-V nitrides in Cl{sub 2}/Ar, CH{sub 4}/H{sub 2}/Ar, ICi/Ar, and IBr/Ar

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vartuli, C.B.; Pearton, S.J.; MacKenzie, J.D.

1996-10-01

The selectivity for etching the binary (GaN, AlN, and InN) and ternary nitrides (InGaN and InAlN) relative to each other in Cl{sub 2}/Ar, CH{sub 4}/H{sub 2}/Ar, ICl/Ar, or IBr/Ar electron cyclotron resonance (ECR) plasmas, and Cl{sub 2}/Ar or CH{sub 4}/H{sub 2}/Ar reactive ion (RIE) plasmas was investigated. Cl-based etches appear to be the best choice for maximizing the selectivity of GaN over the other nitrides. GaN/AlN and GaN/InGaN etch rate ratios of {approximately} 10 were achieved at low RF power in Cl{sub 2}/Ar under ECR and RIE conditions, respectively. GaN/InN selectivity of 10 was found in ICl under ECR conditions.more » A relatively high selectivity (> 6) of InN/GaN was achieved in CH{sub 4}/H{sub 2}/Ar under ECR conditions at low RF powers (50 W). Since the high bond strengths of the nitrides require either high ion energies or densities to achieve practical etch rates it is difficult to achieve high selectivities.« less

Changes in stereoacuity following implantable Collamer lens implantation in patients with myopia

PubMed Central

Khokhar, Sudarshan; Gupta, Shikha; Gogia, Varun; Tewari, Ruchir; Agarwal, Tushar

2015-01-01

The study evaluated the impact of implantable Collamer lens (ICL) implantation on stereoacuity in myopes in a retrospective case series. Ninety-five eyes of 48 patients were recruited. Distance and near stereoacuity were measured using distance Randot stereotest and TNO test, respectively, before surgery and at 4 weeks postoperatively. Mean age of the patients was 23.67 ± 3.7 years. Mean uncorrected distance visual acuity (UDVA) was 1.28 ± 0.37 logarithm of the minimum angle of resolution (logMAR) (median: 1.3; range: 0.3–1.8), and median best-corrected distance visual acuity (BDVA) was 0.18 logMAR (range: 0–0.6). There was a significant improvement in both UDVA and BDVA postsurgery (P < 0.001; Wilcoxon signed rank test). The overall improvement in stereopsis was observed in 15/48 (31.25%) and 13/48 (27.10%) subjects for near and distance, respectively, with no significant difference between the two (P = 0.82; Fisher's exact test). Among stereoblind individuals, the odd's ratio for near stereoacuity to improve in comparison to distance stereoacuity was 8.85 (95% confidence interval: 1.68–46.70; P = 0.01). ICL implantation for refractive correction aided stereoacuity improvement in myopes more so for near. PMID:26655005

The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL*

PubMed Central

Miles, Jennifer A.; Frost, Mark G.; Carroll, Eilis; Rowe, Michelle L.; Howard, Mark J.; Sidhu, Ateesh; Chaugule, Viduth K.; Alpi, Arno F.; Walden, Helen

2015-01-01

The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo. PMID:26149689

The Benefits of Completing Homework for Students with Different Aptitudes in an Introductory Electricity and Magnetism Course

DTIC Science & Technology

2015-02-17

this study, course exams were used to measure student learning rather than research -based concept tests like the Force Concept Inventory [ 19), the...Release Information: This art icles has been accepted by Physical Review Special Topics -- Physics Education Research fo r publication. Previous...portraying official policy. II signed // MONTE D. ANDERSON, Lt Col, USAF Deputy Department Head for Research Department of Physics Tabs 1

Ergonomics and Health Care

DTIC Science & Technology

1994-01-01

consumer ergonomic principles in individual patient treat- products; participating in activities of daily living ment and education, but they have not...psychosocial impacts of illness. Although mists are well aware of the need for implementa- the focus of health care professionals is on patient tion of...h t, a rt icle p rot videe a brief h i ctory’ ol the field of ers,’onomfnicc and explorete the interrelationship beta ee health (tare andi ergjonomic

U.S. EPA, Pesticide Product Label, TRIPLE ACTION 10-6-4 LITE WGT PLNT FD CRABGRSS PREVNTR INSECT CTRL, 04/02/1968

EPA Pesticide Factsheets

2011-04-19

li!"~:'i • 1l1t.

Electrically Tunable Mid-Infrared Single-Mode High-Speed Semiconductor Laser

DTIC Science & Technology

2010-11-01

effective and the net tunnel rate may decrease in spite of progressing carrier density buildup in the accumulation well. Enforcing the bias current at...In te ns ity , a .u . E, eV Regular ICL Figure 4 The dependence of the electroluminescence (EL) quantum energy on the bias voltage for a...spectral maximum energy increases linearly with the bias voltage. Since the dependence is measured in the sub-threshold pumping region, the linear

Wavelengths, energy levels and hyperfine structure of Mn II and Sc II.

NASA Astrophysics Data System (ADS)

Nave, Gillian; Pickering, Juliet C.; Townley-Smith, Keeley I. M.; Hala, .

2015-08-01

For many decades, the Atomic Spectroscopy Groups at the National Institute of Standards and Technology (NIST) and Imperial College London (ICL) have measured atomic data of astronomical interest. Our spectrometers include Fourier transform (FT) spectrometers at NIST and ICL covering the region 1350 Å to 5.5 μm and a 10.7-m grating spectrometer at NIST covering wavelengths from 300 - 5000 Å. Sources for these spectra include high-current continuous and pulsed hollow cathode (HCL) lamps, Penning discharges, and sliding spark discharges. Recent work has focused on the measurement and analysis of wavelengths, energy levels, and hyperfine structure (HFS) constants for iron-group elements. The analysis of FT spectra of Cr I, Mn I, and Mn II is being led by ICL and is described in a companion poster [1]. Current work being led by NIST includes the analysis of HFS in Mn II, analysis of Mn II in the vacuum ultraviolet, and a comprehensive analysis of Sc II.Comprehensive HFS constants for Mn II are needed for the interpretation of stellar spectra and incorrect abundances may be obtained when HFS is omitted. Holt et al. [2] have measured HFS constants for 59 levels of Mn II using laser spectroscopy. We used FT spectra of Mn/Ni and Mn/Cu HCLs covering wavelength ranges from 1350 Å to 5.4 μm to confirm 26 of the A constants of Holt et al. and obtain values for roughly 40 additional levels. We aim to obtain HFS constants for the majority of lines showing significant HFS that are observed in chemically-peculiar stars.Spectra of Sc HCLs have been recorded from 1800 - 6700 Å using a vacuum ultraviolet FT spectrometer at NIST. Additional measurements to cover wavelengths above 6700 Å and below 1800 Å are in progress. The spectra are being analyzed by NIST and Alighar Muslim University, India in order to derive improved wavelengths, energy levels, and hyperfine structure parameters.This work was partially supported by NASA, the STFC and PPARC (UK), the Royal Society of the UK, and the Leverhulme Trust.[1] J. C. Pickering, F. Liggins, C. Clear, M. Ruffoni, G. Nave, C. Sansonetti (this meeting)[2] R. A. Holt, T. J. Scholl & S. D. Rosner, MNRAS 306, 107 (1999)

Refractive Outcomes of 20 Eyes Undergoing ICL Implantation for Correction of Hyperopic Astigmatism.

PubMed

Coskunseven, Efekan; Kavadarli, Isilay; Sahin, Onurcan; Kayhan, Belma; Pallikaris, Ioannis

2017-09-01

To analyze 1-week, 1-month, and 12-month postoperative refractive outcomes of eyes that under-went ICL implantation to correct hyperopic astigmatism. The study enrolled 20 eyes of patients with an average age of 32 years (range: 21 to 40 years). The outcomes of spherical and cylindrical refraction, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), vault, and angle parameters were evaluated 1 week, 1 month, and 12 months postoperatively. The preoperative mean UDVA was 0.15 ± 0.11 (decimal) (20/133 Snellen) and increased to 0.74 ± 0.25 (20/27 Snellen) postoperatively, with a change of 0.59 (decimal) (20/33.9 Snellen) (P < .0001), which was statistically significant. The preoperative mean CDVA was 0.74 ± 0.25 (decimal) (20/27 Snellen) and increased to 0.78 ± 0.21 (20/25 Snellen), with a change of 0.03 (decimal) (20/666 Snellen) (P < .052), which was not statistically significant. The mean preoperative sphere was 6.86 ± 1.77 diopters (D) and the mean preoperative cylinder was -1.44 ± 0.88 D. The mean 12-month postoperative sphere decreased to 0.46 ± 0.89 D (P < .001) and cylinder decreased to -0.61 ± 0.46 D (P < .001), with a change of 6.40 D, both of which were statistically significant. The mean 1-month postoperative vault was 0.65 ± 0.13 mm and decreased to 0.613 ± 0.10 mm at 1 year postoperatively, with a change of 0.44 mm (P < .003). The preoperative/12-month and 1-month/12-month trabecular-iris angle (TIA), trabecular-iris space area 500 mm from the scleral spur (TISA500), and angle opening distance 500 mm from the scleral spur (AOD500) values were analyzed nasally, temporally, and inferiorly. All differences were statistically significant between preoperative/12-month analysis. The only differences between 1- and 12-month analysis were on TISA500 inferior (P < .002) and AOD500 nasal (0.031) values. ICL hyperopic toric implantation is a safe method and provides stable refractive outcomes in patients with high hyperopia (up to 10.00 D) and astigmatism (up to 6.00 D). [J Refract Surg. 2017;33(9):604-609.]. Copyright 2017, SLACK Incorporated.

Martian fluid and Martian weathering signatures identified in Nakhla, NWA 998 and MIL 03346 by halogen and noble gas analysis

NASA Astrophysics Data System (ADS)

Cartwright, J. A.; Gilmour, J. D.; Burgess, R.

2013-03-01

We report argon (Ar) noble gas, Ar-Ar ages and halogen abundances (Cl, Br, I) of Martian nakhlites Nakhla, NWA 998 and MIL 03346 to determine the presence of Martian hydrous fluids and weathering products. Neutron-irradiated samples were either crushed and step-heated (Nakhla only), or simply step-heated using a laser or furnace, and analysed for noble gases using an extension of the 40Ar-39Ar technique to determine halogen abundances. The data obtained provide the first isotopic evidence for a trapped fluid that is Cl-rich, has a strong correlation with 40ArXS (40ArXS = 40Armeasured - 40Arradiogenic) and displays 40ArXS/36Ar of ˜1000 - consistent with the Martian atmosphere. This component was released predominantly in the low temperature and crush experiments, which may suggest a fluid inclusion host. For the halogens, we observe similar Br/Cl and I/Cl ratios between the nakhlites and terrestrial reservoirs, which is surprising given the absence of crustal recycling, organic matter and frequent fluid activity on Mars. In particular, Br/Cl ratios in our Nakhla samples (especially olivine) are consistent with previously analysed Martian weathering products, and both low temperature and crush analyses show a similar trend to the evaporation of seawater. This may indicate that surface brines play an important role on Mars and on halogen assemblages within Martian meteorites and rocks. Elevated I/Cl ratios in the low temperature NWA 998 and MIL 03346 releases may relate to in situ terrestrial contamination, though we are unable to distinguish between low temperature terrestrial or Martian components. Whilst estimates of the amount of water present based on the 36Ar concentrations are too high to be explained by a fluid component alone, they are consistent with a mixed-phase inclusion (gas and fluid) or with shock-implanted Martian atmospheric argon. The observed fluid is dilute (low salinity, but high Br/Cl and I/Cl ratios), contains a Martian atmospheric component, and may represent a mixture of a shallow fluid with one derived from fluid circulation within the nakhlite cumulate pile - with heat for fluid circulation supplied by either the igneous intrusion or by an impact event.

An efficient mass-preserving interface-correction level set/ghost fluid method for droplet suspensions under depletion forces

NASA Astrophysics Data System (ADS)

Ge, Zhouyang; Loiseau, Jean-Christophe; Tammisola, Outi; Brandt, Luca

2018-01-01

Aiming for the simulation of colloidal droplets in microfluidic devices, we present here a numerical method for two-fluid systems subject to surface tension and depletion forces among the suspended droplets. The algorithm is based on an efficient solver for the incompressible two-phase Navier-Stokes equations, and uses a mass-conserving level set method to capture the fluid interface. The four novel ingredients proposed here are, firstly, an interface-correction level set (ICLS) method; global mass conservation is achieved by performing an additional advection near the interface, with a correction velocity obtained by locally solving an algebraic equation, which is easy to implement in both 2D and 3D. Secondly, we report a second-order accurate geometric estimation of the curvature at the interface and, thirdly, the combination of the ghost fluid method with the fast pressure-correction approach enabling an accurate and fast computation even for large density contrasts. Finally, we derive a hydrodynamic model for the interaction forces induced by depletion of surfactant micelles and combine it with a multiple level set approach to study short-range interactions among droplets in the presence of attracting forces.

THE SCATTERING OF K AND Cs BY SEVERAL COMPOUNDS.

DTIC Science & Technology

The nonreactive scattering of K from C10H16, (CH3)3CBr, SiCl4 , Cl2, Br2, I2, ICl, (CN)2C=C(CN)2, and Cs from HBr has been studied in experiments with... SiCl4 , and Cs + HBr and also from the supernumerary rainbows for K + C10H16 and (CH3)3CBr. An optical model analysis on K+(CH3)3CBr and Cs + HBr

Fanconi anemia (cross)linked to DNA repair.

PubMed

Niedernhofer, Laura J; Lalai, Astrid S; Hoeijmakers, Jan H J

2005-12-29

Fanconi anemia is characterized by hypersensitivity to DNA interstrand crosslinks (ICLs) and susceptibility to tumor formation. Despite the identification of numerous Fanconi anemia (FANC) genes, the mechanism by which proteins encoded by these genes protect a cell from DNA interstrand crosslinks remains unclear. The recent discovery of two DNA helicases that, when defective, cause Fanconi anemia tips the balance in favor of the direct involvement of the FANC proteins in DNA repair and the bypass of DNA lesions.

Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening

NASA Astrophysics Data System (ADS)

Kalid, Ori; Mense, Martin; Fischman, Sharon; Shitrit, Alina; Bihler, Hermann; Ben-Zeev, Efrat; Schutz, Nili; Pedemonte, Nicoletta; Thomas, Philip J.; Bridges, Robert J.; Wetmore, Diana R.; Marantz, Yael; Senderowitz, Hanoch

2010-12-01

Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.

Chloride equilibrium potential in salamander cones

PubMed Central

Thoreson, Wallace B; Bryson, Eric J

2004-01-01

Background GABAergic inhibition and effects of intracellular chloride ions on calcium channel activity have been proposed to regulate neurotransmission from photoreceptors. To assess the impact of these and other chloride-dependent mechanisms on release from cones, the chloride equilibrium potential (ECl) was determined in red-sensitive, large single cones from the tiger salamander retinal slice. Results Whole cell recordings were done using gramicidin perforated patch techniques to maintain endogenous Cl- levels. Membrane potentials were corrected for liquid junction potentials. Cone resting potentials were found to average -46 mV. To measure ECl, we applied long depolarizing steps to activate the calcium-activated chloride current (ICl(Ca)) and then determined the reversal potential for the current component that was inhibited by the Cl- channel blocker, niflumic acid. With this method, ECl was found to average -46 mV. In a complementary approach, we used a Cl-sensitive dye, MEQ, to measure the Cl- flux produced by depolarization with elevated concentrations of K+. The membrane potentials produced by the various high K+ solutions were measured in separate current clamp experiments. Consistent with electrophysiological experiments, MEQ fluorescence measurements indicated that ECl was below -36 mV. Conclusions The results of this study indicate that ECl is close to the dark resting potential. This will minimize the impact of chloride-dependent presynaptic mechanisms in cone terminals involving GABAa receptors, glutamate transporters and ICl(Ca). PMID:15579212

The Effect of the Crystalline Lens on Central Vault After Implantable Collamer Lens Implantation.

PubMed

Qi, Meng-Ying; Chen, Qian; Zeng, Qing-Yan

2017-08-01

To identify associations between crystalline lens-related factors and central vault after Implantable Collamer Lens (ICL) (Staar Surgical, Monrovia, CA) implantation. This retrospective clinical study included 320 eyes from 186 patients who underwent ICL implantation surgery. At 1 year after surgery, the central vault was measured using anterior segment optical coherence tomography. Preoperative anterior chamber depth, lens thickness, lens position (lens position = anterior chamber depth + 1/2 lens thickness), and vault were analyzed to investigate the effects of lens-related factors on postoperative vault. The mean vault was 513 ± 215 µm at 1 year after surgery. Vault was positively correlated with preoperative anterior chamber depth (r = 0.495, P < .001) and lens position (r = 0.371, P < .001), but negatively correlated with lens thickness (r = -0.262, P < .001). Eyes with vaults of less than 250 µm had shallower anterior chambers, thicker lenses, and smaller lens position than eyes in the other two vault groups (which had vaults ≥ 250 µm) (P < .001). Eyes with both anterior chamber depth less than 3.1 mm and lens position less than 5.1 mm had greatly reduced vaults (P < .001). The crystalline lens could have an important influence on postoperative vault. Eyes with a shallower anterior chamber and a forward lens position will have lower vaults. [J Refract Surg. 2017;33(8):519-523.]. Copyright 2017, SLACK Incorporated.

The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL.

PubMed

Miles, Jennifer A; Frost, Mark G; Carroll, Eilis; Rowe, Michelle L; Howard, Mark J; Sidhu, Ateesh; Chaugule, Viduth K; Alpi, Arno F; Walden, Helen

2015-08-21

The Fanconi Anemia (FA) DNA repair pathway is essential for the recognition and repair of DNA interstrand crosslinks (ICL). Inefficient repair of these ICL can lead to leukemia and bone marrow failure. A critical step in the pathway is the monoubiquitination of FANCD2 by the RING E3 ligase FANCL. FANCL comprises 3 domains, a RING domain that interacts with E2 conjugating enzymes, a central domain required for substrate interaction, and an N-terminal E2-like fold (ELF) domain. The ELF domain is found in all FANCL homologues, yet the function of the domain remains unknown. We report here that the ELF domain of FANCL is required to mediate a non-covalent interaction between FANCL and ubiquitin. The interaction involves the canonical Ile44 patch on ubiquitin, and a functionally conserved patch on FANCL. We show that the interaction is not necessary for the recognition of the core complex, it does not enhance the interaction between FANCL and Ube2T, and is not required for FANCD2 monoubiquitination in vitro. However, we demonstrate that the ELF domain is required to promote efficient DNA damage-induced FANCD2 monoubiquitination in vertebrate cells, suggesting an important function of ubiquitin binding by FANCL in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

The role of ADP-ribosylation in regulating DNA interstrand crosslink repair

PubMed Central

Gunn, Alasdair R.; Banos-Pinero, Benito; Paschke, Peggy; Sanchez-Pulido, Luis; Ariza, Antonio; Day, Joseph; Emrich, Mehera; Leys, David; Ponting, Chris P.

2016-01-01

ABSTRACT ADP-ribosylation by ADP-ribosyltransferases (ARTs) has a well-established role in DNA strand break repair by promoting enrichment of repair factors at damage sites through ADP-ribose interaction domains. Here, we exploit the simple eukaryote Dictyostelium to uncover a role for ADP-ribosylation in regulating DNA interstrand crosslink repair and redundancy of this pathway with non-homologous end-joining (NHEJ). In silico searches were used to identify a protein that contains a permutated macrodomain (which we call aprataxin/APLF-and-PNKP-like protein; APL). Structural analysis reveals that this permutated macrodomain retains features associated with ADP-ribose interactions and that APL is capable of binding poly(ADP-ribose) through this macrodomain. APL is enriched in chromatin in response to cisplatin treatment, an agent that induces DNA interstrand crosslinks (ICLs). This is dependent on the macrodomain of APL and the ART Adprt2, indicating a role for ADP-ribosylation in the cellular response to cisplatin. Although adprt2− cells are sensitive to cisplatin, ADP-ribosylation is evident in these cells owing to redundant signalling by the double-strand break (DSB)-responsive ART Adprt1a, promoting NHEJ-mediated repair. These data implicate ADP-ribosylation in DNA ICL repair and identify that NHEJ can function to resolve this form of DNA damage in the absence of Adprt2. PMID:27587838

Apoptotic depletion of CD4+ T cells in idiopathic CD4+ T lymphocytopenia.

PubMed Central

Laurence, J; Mitra, D; Steiner, M; Lynch, D H; Siegal, F P; Staiano-Coico, L

1996-01-01

Progressive loss of CD4+ T lymphocytes, accompanied by opportunistic infections characteristic of the acquired immune deficiency syndrome, ahs been reported in the absence of any known etiology. The pathogenesis of this syndrome, a subset of idiopathic CD4+ T lymphocytopenia (ICL), is uncertain. We report that CD4+ T cells from seven of eight ICL patients underwent accelerated programmed cell death, a process facilitated by T cell receptor cross-linking. Apoptosis was associated with enhanced expression of Fas and Fas ligand in unstimulated cell populations, and partially inhibited by soluble anti-Fas mAb. In addition, apoptosis was suppressed by aurintricarboxylic acid, an inhibitor of calcium-dependent endonucleases and proteases, in cells from four of seven patients, The in vivo significance of these findings was supported by three factors: the absence of accelerated apoptosis in persons with stable, physiologic CD4 lymphopenia without clinical immune deficiency; detection of serum antihistone H2B autoantibodies, one consequence of DNA fragmentation, in some patients; and its selectivity, with apoptosis limited to the CD4 population in some, and occurring among CD8+ T cells predominantly in those individuals with marked depletion of both CD4+ T lymphocytes linked to clinical immune suppression have evidence for accelerated T cell apoptosis in vitro that may be pathophysiologic and amenable to therapy with apoptosis inhibitors. PMID:8609222

A new strategy to mitigate the initial capacity loss of lithium ion batteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Xin; Lin, Chikai; Wang, Xiaoping

2016-08-01

Hard carbon (non-graphitizable) and related materials, like tin, tin oxide, silicon, and silicon oxide, have a high theoretical lithium delivery capacity (>550 mAh/g depending on their structural and chemical properties) but unfortunately they also exhibit a large initial capacity loss (ICL) that overrides the true reversible capacity in a full cell. Overcoming the large ICL of hard carbon in a full-cell lithium-ion battery (LIB) necessitates a new strategy wherein a sacrificial lithium source additive, such as, Li5FeO4 (LFO), is inserted on the cathode side. Full batteries using hard carbon coupled with LFO-LiCoO2 (LCO) are currently under development at our laboratory.more » We find that the reversible capacity of a cathode containing LFO can be increased by 14%. Furthermore, the cycle performance of full cells with LFO additive is improved from <90% to >95%. We show that the LFO additive not only can address the irreversible capacity loss of the anode, but can also provide the additional lithium ion source required to mitigate the lithium loss caused by side reactions. In addition, we have explored the possibility to achieve higher capacity with hard carbon, whereby the energy density of full cells can be increased from ca. 300 Wh/kg to >400 Wh/kg.« less

Coupling of HRT II and AS-OCT to evaluate corneal endothelial cell loss and in vivo visualization of the Ahmed glaucoma valve implant.

PubMed

Mendrinos, E; Dosso, A; Sommerhalder, J; Shaarawy, T

2009-09-01

To report corneal endothelial cell loss and in vivo visualization of the Ahmed glaucoma valve implant in eyes with refractory glaucoma. Ten eyes underwent Ahmed valve implant surgery and were followed-up for 12 months. Data collected included intraocular pressure (IOP), number of antiglaucoma medications and surgery-related complications. At 6 and 12 months postoperatively, the intracameral length of the drainage tube (ICL) and the distance between the tube and the cornea (T-C distance), and the iris (T-I distance) were assessed using anterior segment optical coherence tomography (AS-OCT). Heidelberg cornea tomograph II (HRT II) was used to measure the corneal endothelial cell density. Mean (+/-SEM) preoperative IOP was 29.5+/-4 mmHg. Mean postoperative IOP was 11.6+/-2 at 12 months (P<0.01). Over a 6-month period, mean corneal endothelial loss was 7.9%+/-2.5 in the central and 7.5%+/-2.4 in the peripheral cornea (P<0.01). There was no correlation between central or peripheral corneal endothelial cell loss and the T-C, T-I distance or the ICL of the tube. Corneal endothelial cell loss occurs following Ahmed valve implant surgery, this appears to be multifactorial. AS-OCT and HRT II are promising methods for the follow-up of patients with a glaucoma drainage device.

FANCJ Helicase Operates in the Fanconi Anemia DNA Repair Pathway and the Response to Replicational Stress

PubMed Central

Wu, Yuliang; Brosh, Robert M.

2009-01-01

Fanconi anemia (FA) is an autosomal recessive disorder characterized by multiple congenital anomalies, progressive bone marrow failure, and high cancer risk. Cells from FA patients exhibit spontaneous chromosomal instability and hypersensitivity to DNA interstrand cross-linking (ICL) agents. Although the precise mechanistic details of the FA/BRCA pathway of ICL-repair are not well understood, progress has been made in the identification of the FA proteins that are required for the pathway. Among the 13 FA complementation groups from which all the FA genes have been cloned, only a few of the FA proteins are predicted to have direct roles in DNA metabolism. One of the more recently identified FA proteins, shown to be responsible for complementation of the FA complementation group J, is the BRCA1 Associated C-terminal Helicase (BACH1, designated FANCJ), originally identified as a protein associated with breast cancer. FANCJ has been proposed to function downstream of FANCD2 monoubiquitination, a critical event in the FA pathway. Evidence supports a role for FANCJ in a homologous recombination (HR) pathway of double strand break (DSB) repair. In this review, we will summarize the current knowledge in terms of FANCJ functions through its enzymatic activities and protein interactions. The molecular roles of FANCJ in DNA repair and the response to replicational stress will be discussed. PMID:19519404

A New Cell-Free System to Study BRCA1 Function

DTIC Science & Technology

2015-05-01

analyzed by denaturing polyacrylamide gel electrophoresis. UbVS treatment had no effect on the arrival of leading strands at the ICL (Figure 2G in [3...of leading strands to the -1 position, as well as formation of all downstream nascent strand products (Figure 2G in [3], compare lanes 7-11 with 13...17). Addition of free ubiquitin with UbVS restored Approach, Insertion, and Extension, albeit with delayed kinetics (Figure 2G in [3], lanes 19-23

Principles of Work Sample Testing. 1. A Non-Empirical Taxonomy of Test Uses

DTIC Science & Technology

1979-04-01

ARI TECHNICAL REPORT TR-79-A8 Principles of Work Sample Testingi I. A Non-Empirical Taxonomy of Test Uses b y Robert M. Guion BOWLING GREEN STATE...UNIVERSITY % ’ Bowling Green , Ohio 43403 e April 1979 Contract DAHC 19-77-C-0007 Cj Prepared for U.S. ARMY RESEARCH INSTITUTEfor the BEHAVIORAL and...M./io DAlICl9-77-Cji11J7 * 9. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT. PROJECT, TASK Bowling Green State UniversityAEAWOKUINMER

Integration of Manpower, Personnel, and Training Issues from the Materiel System Acquisition Process Into the Planning Programming and Budgeting System

DTIC Science & Technology

1981-03-01

89’" ICL THIS DOCUMENT IS BEST QUALITY AVAILABLE. THE COPY FURNISHED TO DTIC CONTAINED A SIGNIFICANT NUMBER OF PAGES WHICH DO NOT REPRODUCE LEGIBLY. U...S. ARMY RESEARCH INSTITUTE FOR THE BEHAVIORAL AND SOCIAL SCIENCES A Field Operating Agency under the Jurisdiction of the Deputy Chief of Staff for...SUPPLEMENTARY NOTES Col. Frank Bettinger (SSC-NCR), LTC Donald Lyman (DCSPER), and Mr. Jacob Barber (DSCPER) provided valuable input and critical

Middle region of FancM interacts with Mhf and Rmi1 in silkworms, a species lacking the Fanconi anaemia (FA) core complex.

PubMed

Sugahara, R; Mon, H; Lee, J M; Kusakabe, T

2014-04-01

The Fanconi anaemia (FA) pathway is responsible for interstrand crosslink (ICL) repair. Among the FA core complex components, FANCM is believed to act as a damage sensor for the ICL-blocked replication fork and also as a molecular platform for FA core complex assembly and interaction with Bloom's syndrome (BS) complex that is thought to play an important role in the processing of DNA structures such as stalled replication forks. In the present study, we found that in silkworms, Bombyx mori, a species lacking the major FA core complex components (FANCA, B, C, E, F, and G), FancM is required for FancD2 monoubiquitination and cell proliferation in the presence of mitomycin C (MMC). Silkworm FancM (BmFancM) was phosphorylated in the middle regions, and the modification was associated with its subcellular localization. In addition, BmFancM interacted with Mhf1, a histone-fold protein, and Rmi1, a subunit of the BS complex, in the different regions. The interaction region containing at least these two protein-binding domains played an essential role in FancM-dependent resistance to MMC. Our results suggest that BmFancM also acts as a platform for recruitment of both the FA protein and the BS protein, although the silkworm genome seems to lose FAAP24, a FancM-binding partner protein in mammals. © 2013 The Royal Entomological Society.

Non-uniform temperature and species concentration measurements in a laminar flame using multi-band infrared absorption spectroscopy

NASA Astrophysics Data System (ADS)

Ma, Liu Hao; Lau, Lok Yin; Ren, Wei

2017-03-01

We report in situ measurements of non-uniform temperature, H2O and CO2 concentration distributions in a premixed methane-air laminar flame using tunable diode laser absorption spectroscopy (TDLAS). A mid-infrared, continuous-wave, room-temperature interband cascade laser (ICL) at 4183 nm was used for the sensitive detection of CO2 at high temperature.The H2O absorption lines were exploited by one distributed feedback (DFB) diode laser at 1343 nm and one ICL at 2482 nm to achieve multi-band absorption measurements with high species concentration sensitivity, high temperature sensitivity, and immunity to variations in ambient conditions. A novel profile-fitting function was proposed to characterize the non-uniform temperature and species concentrations along the line-of-sight in the flame by detecting six absorption lines of CO2 and H2O simultaneously. The flame temperature distribution was measured at different heights above the burner (5-20 mm), and compared with the thermocouple measurement with heat-transfer correction. Our TDLAS measured temperature of the central flame was in excellent agreement (<1.5% difference) with the thermocouple data.The TDLAS results were also compared with the CFD simulations using a detailed chemical kinetics mechanism (GRI 3.0) and considering the heat loss to the surroundings.The current CFD simulation overpredicted the flame temperature in the gradient region, but was in excellent agreement with the measured temperature and species concentration in the core of the flame.

MUSE spectroscopy and deep observations of a unique compact JWST target, lensing cluster CLIO

NASA Astrophysics Data System (ADS)

Griffiths, Alex; Conselice, Christopher J.; Alpaslan, Mehmet; Frye, Brenda L.; Diego, Jose M.; Zitrin, Adi; Yan, Haojing; Ma, Zhiyuan; Barone-Nugent, Robert; Bhatawdekar, Rachana; Driver, Simon P.; Robotham, Aaron S. G.; Windhorst, Rogier A.; Wyithe, J. Stuart B.

2018-04-01

We present the results of a VLT MUSE/FORS2 and Spitzer survey of a unique compact lensing cluster CLIO at z = 0.42, discovered through the GAMA survey using spectroscopic redshifts. Compact and massive clusters such as this are understudied, but provide a unique prospective on dark matter distributions and for finding background lensed high-z galaxies. The CLIO cluster was identified for follow-up observations due to its almost unique combination of high-mass and dark matter halo concentration, as well as having observed lensing arcs from ground-based images. Using dual band optical and infra-red imaging from FORS2 and Spitzer, in combination with MUSE optical spectroscopy we identify 89 cluster members and find background sources out to z = 6.49. We describe the physical state of this cluster, finding a strong correlation between environment and galaxy spectral type. Under the assumption of an NFW profile, we measure the total mass of CLIO to be M200 = (4.49 ± 0.25) × 1014 M⊙. We build and present an initial strong-lensing model for this cluster, and measure a relatively low intracluster light (ICL) fraction of 7.21 ± 1.53 per cent through galaxy profile fitting. Due to its strong potential for lensing background galaxies and its low ICL, the CLIO cluster will be a target for our 110 h James Webb Space Telescope `Webb Medium-Deep Field' (WMDF) GTO program.

The nuclease hSNM1B/Apollo is linked to the Fanconi anemia pathway via its interaction with FANCP/SLX4.

PubMed

Salewsky, Bastian; Schmiester, Maren; Schindler, Detlev; Digweed, Martin; Demuth, Ilja

2012-11-15

The recessive genetic disorder Fanconi anemia (FA) is clinically characterized by congenital defects, bone marrow failure and an increased incidence of cancer. Cells derived from FA patients exhibit hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents. We have earlier reported a similar cellular phenotype for human cells depleted of hSNM1B/Apollo (siRNA). In fact, hSNM1B/Apollo has a dual role in the DNA damage response and in generation and maintenance of telomeres, the latter function involving interaction with the shelterin protein TRF2. Here we find that ectopically expressed hSNM1B/Apollo co-immunoprecipitates with SLX4, a protein recently identified as a new FA protein, FANCP, and known to interact with several structure-specific nucleases. As shown by immunofluorescence analysis, FANCP/SLX4 depletion (siRNA) resulted in a significant reduction of hSNM1B/Apollo nuclear foci, supporting the functional relevance of this new protein interaction. Interestingly, as an additional consequence of FANCP/SLX4 depletion, we found a reduction of cellular TRF2, in line with its telomere-related function. Finally, analysis of human cells following double knockdown of hSNM1B/Apollo and FANCP/SLX4 indicated that they function epistatically. These findings further substantiate the role of hSNM1B/Apollo in a downstream step of the FA pathway during the repair of DNA ICLs.

A ChIP-chip approach reveals a novel role for transcription factor IRF1 in the DNA damage response.

PubMed

Frontini, Mattia; Vijayakumar, Meeraa; Garvin, Alexander; Clarke, Nicole

2009-03-01

IRF1 is a transcription factor that regulates key processes in the immune system and in tumour suppression. To gain further insight into IRF1's role in these processes, we searched for new target genes by performing chromatin immunoprecipitation coupled to a CpG island microarray (ChIP-chip). Using this approach we identified 202 new IRF1-binding sites with high confidence. Functional categorization of the target genes revealed a surprising cadre of new roles that can be linked to IRF1. One of the major functional categories was the DNA damage response pathway. In order to further validate our findings, we show that IRF1 can regulate the mRNA expression of a number of the DNA damage response genes in our list. In particular, we demonstrate that the mRNA and protein levels of the DNA repair protein BRIP1 [Fanconi anemia gene J (FANC J)] are upregulated after IRF1 over-expression. We also demonstrate that knockdown of IRF1 by siRNA results in loss of BRIP1 expression, abrogation of BRIP1 foci after DNA interstrand crosslink (ICL) damage and hypersensitivity to the DNA crosslinking agent, melphalan; a characteristic phenotype of FANC J cells. Taken together, our data provides a more complete understanding of the regulatory networks controlled by IRF1 and reveals a novel role for IRF1 in regulating the ICL DNA damage response.

A ChIP–chip approach reveals a novel role for transcription factor IRF1 in the DNA damage response

PubMed Central

Frontini, Mattia; Vijayakumar, Meeraa; Garvin, Alexander; Clarke, Nicole

2009-01-01

IRF1 is a transcription factor that regulates key processes in the immune system and in tumour suppression. To gain further insight into IRF1's role in these processes, we searched for new target genes by performing chromatin immunoprecipitation coupled to a CpG island microarray (ChIP–chip). Using this approach we identified 202 new IRF1-binding sites with high confidence. Functional categorization of the target genes revealed a surprising cadre of new roles that can be linked to IRF1. One of the major functional categories was the DNA damage response pathway. In order to further validate our findings, we show that IRF1 can regulate the mRNA expression of a number of the DNA damage response genes in our list. In particular, we demonstrate that the mRNA and protein levels of the DNA repair protein BRIP1 [Fanconi anemia gene J (FANC J)] are upregulated after IRF1 over-expression. We also demonstrate that knockdown of IRF1 by siRNA results in loss of BRIP1 expression, abrogation of BRIP1 foci after DNA interstrand crosslink (ICL) damage and hypersensitivity to the DNA crosslinking agent, melphalan; a characteristic phenotype of FANC J cells. Taken together, our data provides a more complete understanding of the regulatory networks controlled by IRF1 and reveals a novel role for IRF1 in regulating the ICL DNA damage response. PMID:19129219

[Impact of CHA2DS2 VASc score on substrate for persistent atrial fibrillation and outcome post catheter ablation of atrial fibrillation].

PubMed

Ribo, Tang; Jianzeng, Dong; Xiaohui, Liu; Meisheng, Shang; Ronghui, Yu; Deyong, Long; Xin, Du; Junping, Kang; Jiahui, Wu; Man, Ning; Caihua, Sang; Chenxi, Jiang; Rong, Bai; Songnan, Li; Yan, Yao; Songnan, Wen; Changsheng, Ma

2015-08-01

To explore if CHA2DS2 VASc score can predict substrate for persistent atrial fibrillation ( AF) and outcome post catheter ablation of AF. From January 2011 to December 2012,116 patients underwent catheter ablation of persistent AF in our department and were enrolled in this study. CHA2DS2VASc score was calculated as follows: two points were assigned for a history of stroke or transient ischemic attack and age ≥ 75 and 1 point each was assigned for age ≥ 65, a history of hypertension, diabetes,recent cardiac failure, vessel disease, female. Left atrial geometry ( LA) was reconstructed with a 3.5 mm tip ablation catheter with fill-in threshold 10 in CARTO system. The mapping catheter was stabled at each endocardial location for at least 3 seconds for recording. The electrogram recordings at each endocardial location were analyzed with a custom software embedded in the CARTO mapping system. Interval confidence level (ICL) was used to characterize complex fractionated atrial electrograms (CFAEs) . As the default setting of the software, ICL more than or equal to 7 was considered sites with a highly repetitive CFAEs complex. CFAEs index was defined as the fraction of area of ICL more than or equal to 7 to the left atrial surface. The CFAEs index and outcome of catheter ablation among different CHA2DS2VASc groups were compared. Of the 116 patients, CHA2DS2VASc was 0 in 33 patients, 1 in 31 patients and ≥ 2 in 52 patients. Left atrial surface ((121.2 ± 18.9) cm2, (133.6 ± 23.8) cm2, (133.9 ± 16.1) cm2, P = 0.008), left atrial volume ((103.6 ± 24.8) ml, (118.3 ± 27.8) ml, (120.9 ± 20.9) ml, P = 0.005) and CFAEs index (44.6% ± 22.4%, 54.2% ± 22.2%, 58.7% ± 23.1%, P = 0.023) increased in proportion with increasing CHA2DS2VASc. ICLmax, ICLmin and CFAEs spatial distribution were similar among the three groups. During the mean follow-up of (13 ± 8) months, the recurrence rate were 36.4%, 35.5%, 55.8% among the three groups (P = 0.025). A high CHA2DS2VASc score is associated with extensive AF substrate and higher recurrence rate post catheter ablation of persistent AF.

Inhibition to excitation ratio regulates visual system responses and behavior in vivo.

PubMed

Shen, Wanhua; McKeown, Caroline R; Demas, James A; Cline, Hollis T

2011-11-01

The balance of inhibitory to excitatory (I/E) synaptic inputs is thought to control information processing and behavioral output of the central nervous system. We sought to test the effects of the decreased or increased I/E ratio on visual circuit function and visually guided behavior in Xenopus tadpoles. We selectively decreased inhibitory synaptic transmission in optic tectal neurons by knocking down the γ2 subunit of the GABA(A) receptors (GABA(A)R) using antisense morpholino oligonucleotides or by expressing a peptide corresponding to an intracellular loop of the γ2 subunit, called ICL, which interferes with anchoring GABA(A)R at synapses. Recordings of miniature inhibitory postsynaptic currents (mIPSCs) and miniature excitatory PSCs (mEPSCs) showed that these treatments decreased the frequency of mIPSCs compared with control tectal neurons without affecting mEPSC frequency, resulting in an ∼50% decrease in the ratio of I/E synaptic input. ICL expression and γ2-subunit knockdown also decreased the ratio of optic nerve-evoked synaptic I/E responses. We recorded visually evoked responses from optic tectal neurons, in which the synaptic I/E ratio was decreased. Decreasing the synaptic I/E ratio in tectal neurons increased the variance of first spike latency in response to full-field visual stimulation, increased recurrent activity in the tectal circuit, enlarged spatial receptive fields, and lengthened the temporal integration window. We used the benzodiazepine, diazepam (DZ), to increase inhibitory synaptic activity. DZ increased optic nerve-evoked inhibitory transmission but did not affect evoked excitatory currents, resulting in an increase in the I/E ratio of ∼30%. Increasing the I/E ratio with DZ decreased the variance of first spike latency, decreased spatial receptive field size, and lengthened temporal receptive fields. Sequential recordings of spikes and excitatory and inhibitory synaptic inputs to the same visual stimuli demonstrated that decreasing or increasing the I/E ratio disrupted input/output relations. We assessed the effect of an altered I/E ratio on a visually guided behavior that requires the optic tectum. Increasing and decreasing I/E in tectal neurons blocked the tectally mediated visual avoidance behavior. Because ICL expression, γ2-subunit knockdown, and DZ did not directly affect excitatory synaptic transmission, we interpret the results of our study as evidence that partially decreasing or increasing the ratio of I/E disrupts several measures of visual system information processing and visually guided behavior in an intact vertebrate.

Improving Fatty Acid Availability for Bio-Hydrocarbon Production in Escherichia coli by Metabolic Engineering

PubMed Central

Lin, Fengming; Chen, Yu; Levine, Robert; Lee, Kilho; Yuan, Yingjin; Lin, Xiaoxia Nina

2013-01-01

Previous studies have demonstrated the feasibility of producing fatty-acid-derived hydrocarbons in Escherichia coli. However, product titers and yields remain low. In this work, we demonstrate new methods for improving fatty acid production by modifying central carbon metabolism and storing fatty acids in triacylglycerol. Based on suggestions from a computational model, we deleted seven genes involved in aerobic respiration, mixed-acid fermentation, and glyoxylate bypass (in the order of cyoA, nuoA, ndh, adhE, dld, pta, and iclR) to modify the central carbon metabolic/regulatory networks. These gene deletions led to increased total fatty acids, which were the highest in the mutants containing five or six gene knockouts. Additionally, when two key enzymes in the fatty acid biosynthesis pathway were over-expressed, we observed further increase in strain △cyoA△adhE△nuoA△ndh△pta△dld, leading to 202 mg/g dry cell weight of total fatty acids, ~250% of that in the wild-type strain. Meanwhile, we successfully introduced a triacylglycerol biosynthesis pathway into E. coli through heterologous expression of wax ester synthase/acyl-coenzyme:diacylglycerol acyltransferase (WS/DGAT) enzymes. The added pathway improved both the amount and fuel quality of the fatty acids. These new metabolic engineering strategies are providing promising directions for future investigation. PMID:24147139

Flow immune photoacoustic sensor for real-time and fast sampling of trace gases

NASA Astrophysics Data System (ADS)

Petersen, Jan C.; Balslev-Harder, David; Pelevic, Nikola; Brusch, Anders; Persijn, Stefan; Lassen, Mikael

2018-02-01

A photoacoustic (PA) sensor for fast and real-time gas sensing is demonstrated. The PA cell has been designed for flow noise immunity using computational fluid dynamics (CFD) analysis. PA measurements were conducted at different flow rates by exciting molecular C-H stretch vibrational bands of hexane (C6H14) in clean air at 2950cm-1 (3.38 μm) with a custom made mid-infrared interband cascade laser (ICL). The PA sensor will contribute to solve a major problem in a number of industries using compressed air by the detection of oil contaminants in high purity compressed air. We observe a (1σ, standard deviation) sensitivity of 0.4 +/-0.1 ppb (nmol/mol) for hexane in clean air at flow rates up to 2 L/min, corresponding to a normalized noise equivalent absorption (NNEA) coefficient of 2.5×10-9 W cm-1 Hz1/2, thus demonstrating high sensitivity and fast and real-time gas analysis. The PA sensor is not limited to molecules with C-H stretching modes, but can be tailored to measure any trace gas by simply changing the excitation wavelength (i.e. the laser source) making it useful for many different applications where fast and sensitive trace gas measurements are needed.

Instability, rupture and fluctuations in thin liquid films: Theory and computations

NASA Astrophysics Data System (ADS)

Gvalani, Rishabh; Duran-Olivencia, Miguel; Kalliadasis, Serafim; Pavliotis, Grigorios

2017-11-01

Thin liquid films are ubiquitous in natural phenomena and technological applications. They are commonly studied via deterministic hydrodynamic equations, but thermal fluctuations often play a crucial role that still needs to be understood. An example of this is dewetting, which involves the rupture of a thin liquid film and the formation of droplets. Such a process is thermally activated and requires fluctuations to be taken into account self-consistently. Here we present an analytical and numerical study of a stochastic thin-film equation derived from first principles. We scrutinise the behaviour of the stochastic thin film equation in the limit of perfectly correlated noise along the wall-normal direction. We also perform Monte Carlo simulations of the stochastic equation by adopting a numerical scheme based on a spectral collocation method. The numerical scheme allows us to explore the fluctuating dynamics of the thin film and the behaviour of the system's free energy close to rupture. Finally, we also study the effect of the noise intensity on the rupture time, which is in good agreement with previous works. Imperial College London (ICL) President's PhD Scholarship; European Research Council Advanced Grant No. 247031; EPSRC Grants EP/L025159, EP/L020564, EP/P031587, EP/L024926, and EP/L016230/1.

Measurement Systems Advisory Group

DTIC Science & Technology

1974-04-01

US NavyLib MSAG- 1 REPORT 001 qL5 ID I APRIL 1974 MA2C91SMAR 2 0 19 81 F Prepared For "LONG RANGE ACOUSTIC PROPAGATION PROJECT 7 opt/ icl S[ D _STRIBU...34 j •( - _> ...ailability Codes IV !VM Avail and/or -~’Dist IspecialL K OFFICE OF NAVAL RESEARCH Department of the Navy Washington, D.C.I L 1 April 23...respect and very much appreciated. The report will be distributed to selected members of the user community for their information and comment. Because 1

Compact TDLAS based sensor design using interband cascade lasers for mid-IR trace gas sensing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Lei; Tittel, Frank K.; Li, Chunguang

2016-02-25

Two compact TDLAS sensor systems based on different structural optical cores were developed. The two optical cores combine two recent developments, gallium antimonide (GaSb)-based ICL and a compact multipass gas cell (MPGC) with the goal to create compact TDLAS based sensors for the mid-IR gas detection with high detection sensitivity and low power consumption. The sensors achieved minimum detection limits of ~5 ppbv and ~8 ppbv, respectively, for CH 4 and C 2H 6 concentration measurements with a 3.7-W power consumption.

Effects of Oscillation Frequency and Amplitude on Separation in an Unsteady Turbulent Flow.

DTIC Science & Technology

1980-09-01

be performed with much of the aircraft immersed in turbulent flow. When in operation near the ground or landing platform , unsteady, turbulent flow...34 - .-,...i ,aXa. 8O- IDa I"l N 0 N( ’A0 󈧨 a r. 0 a 0.a " - M - if l’ . t 1 - o t I.- I.- 𔃻 I I I Ni ilNl 1i * 11 it O ag 0) - -i "NUm M CA myp WiX ~ U’iCL

Local Free Space Mapping and Path Guidance,

DTIC Science & Technology

1987-03-01

Free Space Mapping and Path Guidance 12. PERSONIAL UTI4OFS) William T. Cex and Nancy L. Campbell 1s. TYPE OF REPORT 13b. iME COVERED 14. DATE OF REPORT...84 JAN 52 A" 1OMON MAYBOfUSED NMlLEMIAUSTEO UNCLASSIFIED ALL OTHE EDTIN A’.SL Y2.7cesson For 7 *5~ IT D, TA ........... iCL ... . LOCAL FREE SPACE ... MAPPING AND PATH GUIDANCE By Distribuition/ Availabiliuy C0e William T. Gex and Nancy L. Campbell I Avail and/or Naval Ocean Systems Center ist speci1 l

Epi-Side-Down Mounting of Interband Cascade Lasers for Army Applications

DTIC Science & Technology

2006-11-01

retain the principal advantage of electron recycling . However, unlike the QCL, the ICL relies on the cascading of interband optical transitions as...9.0 Cu 393 17 SiC 120 4 AlN 230 (high grade –Tsekoun 2006) 4.5, 4.3 Indium 83.7 24.8@ 20C 2 device ridge and an effective heat spreader ...65.3 K/W M271 epi-side down 8-μm x 1-mm mesa TmaxCW= 212K 4 were vital and survived multiple cryogenic to room temperature recyclings . Fig. 4

Inhibitory effects of marine-derived DNA-binding anti-tumour tetrahydroisoquinolines on the Fanconi anaemia pathway.

PubMed

Martínez, Sandra; Pérez, Laura; Galmarini, Carlos M; Aracil, Miguel; Tercero, Juan C; Gago, Federico; Albella, Beatriz; Bueren, Juan A

2013-10-01

We have previously shown that cells with a defective Fanconi anaemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anti-cancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand cross link (ICL). Here we expand these observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells. Initially, the sensitivity of transformed and untransformed cells, deficient or not in one component of the FA pathway, to mitomycin C (MMC) and three DBATs, trabectedin, Zalypsis and PM01183, was assessed. Then, the functional interaction of these drugs with the FA pathway was comparatively investigated. While untransformed FA-deficient haematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells were hypersensitive to MMC. Furthermore, while MMC always activated the FA pathway, the DBATs inhibited the FA pathway in the cancer cell lines tested and this enhanced their response to MMC. Our data show that although DBATs functionally interact with DNA as do agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors rather than activators. Moreover, this effect was most significant in a variety of cancer cells. These inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of 'fanconizing' cancer cells in order to make them more sensitive to other anti-tumour drugs. © 2013 The British Pharmacological Society.

Searching for Controlled Trials of Complementary and Alternative Medicine: A Comparison of 15 Databases

PubMed Central

Cogo, Elise; Sampson, Margaret; Ajiferuke, Isola; Manheimer, Eric; Campbell, Kaitryn; Daniel, Raymond; Moher, David

2011-01-01

This project aims to assess the utility of bibliographic databases beyond the three major ones (MEDLINE, EMBASE and Cochrane CENTRAL) for finding controlled trials of complementary and alternative medicine (CAM). Fifteen databases were searched to identify controlled clinical trials (CCTs) of CAM not also indexed in MEDLINE. Searches were conducted in May 2006 using the revised Cochrane highly sensitive search strategy (HSSS) and the PubMed CAM Subset. Yield of CAM trials per 100 records was determined, and databases were compared over a standardized period (2005). The Acudoc2 RCT, Acubriefs, Index to Chiropractic Literature (ICL) and Hom-Inform databases had the highest concentrations of non-MEDLINE records, with more than 100 non-MEDLINE records per 500. Other productive databases had ratios between 500 and 1500 records to 100 non-MEDLINE records—these were AMED, MANTIS, PsycINFO, CINAHL, Global Health and Alt HealthWatch. Five databases were found to be unproductive: AGRICOLA, CAIRSS, Datadiwan, Herb Research Foundation and IBIDS. Acudoc2 RCT yielded 100 CAM trials in the most recent 100 records screened. Acubriefs, AMED, Hom-Inform, MANTIS, PsycINFO and CINAHL had more than 25 CAM trials per 100 records screened. Global Health, ICL and Alt HealthWatch were below 25 in yield. There were 255 non-MEDLINE trials from eight databases in 2005, with only 10% indexed in more than one database. Yield varied greatly between databases; the most productive databases from both sampling methods were Acubriefs, Acudoc2 RCT, AMED and CINAHL. Low overlap between databases indicates comprehensive CAM literature searches will require multiple databases. PMID:19468052

Can the PHS model (ISO7933) predict reasonable thermophysiological responses while wearing protective clothing in hot environments?

PubMed

Wang, Faming; Kuklane, Kalev; Gao, Chuansi; Holmér, Ingvar

2011-02-01

In this paper, the prediction accuracy of the PHS (predicted heat strain) model on human physiological responses while wearing protective clothing ensembles was examined. Six human subjects (aged 29 ± 3 years) underwent three experimental trials in three different protective garments (clothing thermal insulation I(cl) ranges from 0.63 to 2.01 clo) in two hot environments (40 °C, relative humidities: 30% and 45%). The observed and predicted mean skin temperature, core body temperature and sweat rate were presented and statistically compared. A significant difference was found in the metabolic rate between FIRE (firefighting clothing) and HV (high visibility clothing) or MIL (military clothing) (p < 0.001). Also, the development of heart rate demonstrated the significant effects of the exposure time and clothing ensembles. In addition, the predicted evaporation rate during HV, MIL and FIRE was much lower than the experimental values. Hence, the current PHS model is not applicable for protective clothing with intrinsic thermal insulations above 1.0 clo. The results showed that the PHS model generated unreliable predictions on body core temperature when human subjects wore thick protective clothing such as firefighting clothing (I(cl) > 1.0 clo). The predicted mean skin temperatures in three clothing ensembles HV, MIL and FIRE were also outside the expected limits. Thus, there is a need for further extension for the clothing insulation validation range of the PHS model. It is recommended that the PHS model should be amended and validated by individual algorithms, physical or physiological parameters, and further subject studies.

Etude analytique et numérique de la réponse en vibration à hautes fréquences d'éprouvettes de fatigue vibratoire des métaux. Application aux aciers

NASA Astrophysics Data System (ADS)

Ben Aich, A.; El Kihel, B.; Kifani, A.; Sahban, F.

1994-07-01

In the present paper, the so-called " ultrasonic fatigue " or fatigue at very high frequency has been studied in the materials elastic behaviour case while neglecting the thermal effects that influence the mechanical fields. The determination of mechanical fields and specimen resonance length has been done both analytically and numerically. The numerical method used for this calculation is the finite element method (FEM). Martensitic steel " Soleil A2 " and austenitic steel " ICL 472 BC " have been considered in order to compare the two methods (analytical and numerical). It is shown that a perfect convergence is obtained between the two solutions. Dans le présent travail, la fatigue vibratoire a été étudiée dans le cas du comportement élastique des matériaux en négligeant les effets thermiques pouvant influencer les champs mécaniques. La détermination de ces champs et de la longueur de résonance des éprouvettes de fatigue a été faite analytiquement et numériquement. Le calcul numérique effectué se base sur la méthode des éléments finis. Dans le but d'une comparaison des solutions analytiques et numériques, deux aciers ont été considérés : un acier martensitique (Soleil A2) et un acier austénitique de type 18-10 (ICL 472 BC). Une parfaite convergence est obtenue entre les deux solutions.

Physiological and enzymatic alterations in sesame seeds submitted to different osmotic potentials.

PubMed

Pires, R M O; Àvila, M A B; Leite, D G; Santos, H O; Souza, G A; Von Pinho, E V R

2017-08-17

With the imminence of global climate changes that affect the temperature and the rainfall uniformity, it is growing the concern about the adaptation of crops to the water deficit. Thus, the objective of this study was to evaluate alterations in physiological and enzymatic mechanisms during the germination process of sesame seeds under different water availability. To simulate the water restriction we used PEG6000, a high molecular weight molecule that does not penetrate the seed structure but allows different osmotic potentials. The treatments were -0.1, -0.2, and -0.3 MPa, and the control. Germination, first-count germination, germination velocity index, and length and dry mass of the hypocotyl and radicle were performed. The seeds were weighed before and after treatments every 3 h. After each weighing, 100 seeds were taken for analysis of the enzymes alcohol dehydrogenase (ADH), malate dehydrogenase, esterase, catalase (CAT), superoxide dismutase (SOD), isocitrate lyase (ICL), and glutamate dehydrogenase (GTDH). The statistical design was completely randomized with five replications. PEG6000 prolonged ADH activity during the beginning of germination, maintaining the anaerobic metabolism for longer. Subsequently, their activity was reduced, as well as ICL, favoring the deterioration of the seeds that take the time to germinate. Behavior was evidenced by the appearance of SOD, CAT, and GTDH isoforms after 24 h of imbibition when water restriction was imposed. Therefore, the PEG600 is efficient in simulating water deficit conditions in future scenarios of climate change, offering impotent information regarding the germination behavior of the plants under these conditions.

Searching for controlled trials of complementary and alternative medicine: a comparison of 15 databases.

PubMed

Cogo, Elise; Sampson, Margaret; Ajiferuke, Isola; Manheimer, Eric; Campbell, Kaitryn; Daniel, Raymond; Moher, David

2011-01-01

This project aims to assess the utility of bibliographic databases beyond the three major ones (MEDLINE, EMBASE and Cochrane CENTRAL) for finding controlled trials of complementary and alternative medicine (CAM). Fifteen databases were searched to identify controlled clinical trials (CCTs) of CAM not also indexed in MEDLINE. Searches were conducted in May 2006 using the revised Cochrane highly sensitive search strategy (HSSS) and the PubMed CAM Subset. Yield of CAM trials per 100 records was determined, and databases were compared over a standardized period (2005). The Acudoc2 RCT, Acubriefs, Index to Chiropractic Literature (ICL) and Hom-Inform databases had the highest concentrations of non-MEDLINE records, with more than 100 non-MEDLINE records per 500. Other productive databases had ratios between 500 and 1500 records to 100 non-MEDLINE records-these were AMED, MANTIS, PsycINFO, CINAHL, Global Health and Alt HealthWatch. Five databases were found to be unproductive: AGRICOLA, CAIRSS, Datadiwan, Herb Research Foundation and IBIDS. Acudoc2 RCT yielded 100 CAM trials in the most recent 100 records screened. Acubriefs, AMED, Hom-Inform, MANTIS, PsycINFO and CINAHL had more than 25 CAM trials per 100 records screened. Global Health, ICL and Alt HealthWatch were below 25 in yield. There were 255 non-MEDLINE trials from eight databases in 2005, with only 10% indexed in more than one database. Yield varied greatly between databases; the most productive databases from both sampling methods were Acubriefs, Acudoc2 RCT, AMED and CINAHL. Low overlap between databases indicates comprehensive CAM literature searches will require multiple databases.

Hemispheric asymmetry of macroscopic and elementary calcium signals mediated by InsP3 in Xenopus oocytes.

PubMed

Callamaras, N; Sun, X P; Ivorra, I; Parker, I

1998-09-01

1. The mechanisms underlying hemispheric asymmetry of the inositol 1, 4,5-trisphosphate (InsP3)-calcium signalling pathway in Xenopus oocytes were examined by fluorescence imaging of calcium signals and recording calcium-activated Cl- currents (ICl,Ca) evoked by intracellular calcium injections and photorelease of InsP3. 2. The maximal ICl,Ca evoked by strong photorelease of InsP3 was 8 times greater in the animal than the vegetal hemisphere, but the average threshold amounts of InsP3 required to evoke detectable currents were similar in each hemisphere. 3. Currents evoked by injections of calcium were about 2.5 times greater near the animal pole than near the vegetal pole, whereas fluorescence signals evoked by injections were similar in each hemisphere. 4. Calcium waves were evoked by photolysis flashes of similar strengths in both hemispheres of albino oocytes, but peak calcium levels evoked by supramaximal stimuli were 70 % greater in the animal hemisphere. 5. Elementary calcium release events (puffs) in the animal hemisphere had amplitudes about double that in the vegetal hemisphere, and more often involved coupled release from adjacent sites. Calcium release sites were more closely packed in the animal hemisphere, with a mean spacing of about 1.5 micro m compared with 2.25 micro m in the vegetal hemisphere. 6. The larger amplitude of currents mediated by InsP3 in the animal hemisphere, therefore, involves an increased flux of calcium at individual release units, a more dense packing of release units and a higher density of Cl- channels.

Hemispheric asymmetry of macroscopic and elementary calcium signals mediated by InsP3 in Xenopus oocytes

PubMed Central

Callamaras, Nick; Sun, Xiao-Ping; Ivorra, Isabel; Parker, Ian

1998-01-01

The mechanisms underlying hemispheric asymmetry of the inositol 1,4,5-trisphosphate (InsP3)-calcium signalling pathway in Xenopus oocytes were examined by fluorescence imaging of calcium signals and recording calcium-activated Cl− currents (ICl,Ca) evoked by intracellular calcium injections and photorelease of InsP3. The maximal ICl,Ca evoked by strong photorelease of InsP3 was 8 times greater in the animal than the vegetal hemisphere, but the average threshold amounts of InsP3 required to evoke detectable currents were similar in each hemisphere. Currents evoked by injections of calcium were about 2.5 times greater near the animal pole than near the vegetal pole, whereas fluorescence signals evoked by injections were similar in each hemisphere. Calcium waves were evoked by photolysis flashes of similar strengths in both hemispheres of albino oocytes, but peak calcium levels evoked by supramaximal stimuli were 70% greater in the animal hemisphere. Elementary calcium release events (puffs) in the animal hemisphere had amplitudes about double that in the vegetal hemisphere, and more often involved coupled release from adjacent sites. Calcium release sites were more closely packed in the animal hemisphere, with a mean spacing of about 1.5 μm compared with 2.25 μm in the vegetal hemisphere. The larger amplitude of currents mediated by InsP3 in the animal hemisphere, therefore, involves an increased flux of calcium at individual release units, a more dense packing of release units and a higher density of Cl− channels. PMID:9706018

Inhibitory effects of marine-derived DNA-binding anti-tumour tetrahydroisoquinolines on the Fanconi anaemia pathway

PubMed Central

Martínez, Sandra; Pérez, Laura; Galmarini, Carlos M; Aracil, Miguel; Tercero, Juan C; Gago, Federico; Albella, Beatriz; Bueren, Juan A

2013-01-01

BACKGROUND AND PURPOSE We have previously shown that cells with a defective Fanconi anaemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anti-cancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand cross link (ICL). Here we expand these observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells. EXPERIMENTAL APPROACH Initially, the sensitivity of transformed and untransformed cells, deficient or not in one component of the FA pathway, to mitomycin C (MMC) and three DBATs, trabectedin, Zalypsis and PM01183, was assessed. Then, the functional interaction of these drugs with the FA pathway was comparatively investigated. KEY RESULTS While untransformed FA-deficient haematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells were hypersensitive to MMC. Furthermore, while MMC always activated the FA pathway, the DBATs inhibited the FA pathway in the cancer cell lines tested and this enhanced their response to MMC. CONCLUSIONS AND IMPLICATIONS Our data show that although DBATs functionally interact with DNA as do agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors rather than activators. Moreover, this effect was most significant in a variety of cancer cells. These inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of ‘fanconizing’ cancer cells in order to make them more sensitive to other anti-tumour drugs. PMID:23937566

Targeting Homologous Recombination by Pharmacological Inhibitors Enhances the Killing Response of Glioblastoma Cells Treated with Alkylating Drugs.

PubMed

Berte, Nancy; Piée-Staffa, Andrea; Piecha, Nadine; Wang, Mengwan; Borgmann, Kerstin; Kaina, Bernd; Nikolova, Teodora

2016-11-01

Malignant gliomas exhibit a high level of intrinsic and acquired drug resistance and have a dismal prognosis. First- and second-line therapeutics for glioblastomas are alkylating agents, including the chloroethylating nitrosoureas (CNU) lomustine, nimustine, fotemustine, and carmustine. These agents target the tumor DNA, forming O 6 -chloroethylguanine adducts and secondary DNA interstrand cross-links (ICL). These cross-links are supposed to be converted into DNA double-strand breaks, which trigger cell death pathways. Here, we show that lomustine (CCNU) with moderately toxic doses induces ICLs in glioblastoma cells, inhibits DNA replication fork movement, and provokes the formation of DSBs and chromosomal aberrations. Since homologous recombination (HR) is involved in the repair of DSBs formed in response to CNUs, we elucidated whether pharmacologic inhibitors of HR might have impact on these endpoints and enhance the killing effect. We show that the Rad51 inhibitors RI-1 and B02 greatly ameliorate DSBs, chromosomal changes, and the level of apoptosis and necrosis. We also show that an inhibitor of MRE11, mirin, which blocks the formation of the MRN complex and thus the recognition of DSBs, has a sensitizing effect on these endpoints as well. In a glioma xenograft model, the Rad51 inhibitor RI-1 clearly enhanced the effect of CCNU on tumor growth. The data suggest that pharmacologic inhibition of HR, for example by RI-1, is a reasonable strategy for enhancing the anticancer effect of CNUs. Mol Cancer Ther; 15(11); 2665-78. ©2016 AACR. ©2016 American Association for Cancer Research.

Development for equipment of the milk macromolecules content detection

NASA Astrophysics Data System (ADS)

Ding, Guochao; Li, Weimin; Shang, Tingyi; Xi, Yang; Gao, Yunli; Zhou, Zhen

Developed an experimental device for rapid and accurate detection of milk macromolecular content. This device developed based on laser scattered through principle, the principle use of the ingredients of the scattered light and transmitted light ratio characterization of macromolecules. Peristaltic pump to achieve automatic input and output of the milk samples, designing weak signal detection amplifier circuit for detecting the ratio with ICL7650. Real-time operating system μC / OS-II is the core design of the software part of the whole system. The experimental data prove that the device can achieve a fast real-time measurement of milk macromolecules.

CNA’s Integrated Ship Database: Third Quarter CY 2012 Update

DTIC Science & Technology

2013-11-01

rogram!- -;OJ"’T’-" A "’K"C~¥-go"Shi"~P:----------------t---’~;;1~ ® T- AKR Veh icle-Car o 9 S T- ADT Tran rt 0i1er 1 9 Mitita.y Sealift Command (MSC). in...CNA’s Integrated Ship Database Third Quarter CY 2012 Update Gregory N. Suess • Lynette A . McClain • Linette O. Neal CNA Interactive Software DIS...law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB

The Hereptofauna of Letterkenny Army Depot, South-Central Pennsylvania: A Starting Point to the Long-Term Monitoring and Management of Amphibians and Reptiles

DTIC Science & Technology

2010-06-01

Journal of Kansas Herpetology Number 34 (June 2010) 11 www.cnah.org/khs ARtIClES tHE HERpEtofAUNA of lEttERKENNY ARMY dEpot, SoUtH-CENtRAl...compare the herpetological commu- nity currently present at the site with that expected from prior literature (felbaum, 1995; Hulse et al., 2001; tetra...Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 Journal of Kansas Herpetology Number 34 (June 2010) 12 www.cnah.org/khs agricultural and other

Ada Compiler Validation Summary Report. Certificate Number 880728S1. 09141 DDC-I, Inc., DACS-386/UNIX, Version 4.2, ICL DRS 300 Host and Target

DTIC Science & Technology

1988-07-28

r R ~l~ F COPV en Data Entered) AT ION PAGE -ErOP RCoMrE-EoNGFOP. A D-A 204 928 1Z. GOVT ACCESSION NO. 3. RECIPIENT’S CATALOG NUMBER 4...PAGE (When Data Entered) Ada Compiler Validation Summary Repor-: Compiler Name: DACS-386/UNIX, Version 4.2 Certificate Number: 880728S1.09141 Host...which have the STORAGE SIZE length clause were changed to comment lines under the direction of the AVF Manager . These modified tests ran to a successful

Nonlinear Fault Diagnosis,

DTIC Science & Technology

1981-05-01

obtained if one first generates a data base in terms cf the nominal circuit parameters and then extracts the aocrooriate s’pnbo𔃾c transfer functicn from...0 0 0 0 I 0 I 0 0 0 0 Here we initially allow V0 , ICl , VRA ,and IE to be taken as test outputs. The measure of testability 6min is used to extract ...C C IN QQ2M + VB2 R5 R L V 0 LO R2 R Fig. 4 Direct-Coupled Two-Stage Amplifier The component-connection equations for Mode 2 analysis are: VR1 0 0 0 0

The contribution of hydrothermally altered ocean crust to the mantle halogen and noble gas cycles

NASA Astrophysics Data System (ADS)

Chavrit, Déborah; Burgess, Ray; Sumino, Hirochika; Teagle, Damon A. H.; Droop, Giles; Shimizu, Aya; Ballentine, Chris J.

2016-06-01

Recent studies suggest that seawater-derived noble gases and halogens are recycled into the deep mantle by the subduction of oceanic crust. To understand the processes controlling the availability of halogens and noble gases for subduction, we determined the noble gas elemental and isotopic ratios and halogen (Cl, Br, I) concentrations in 28 igneous samples from the altered oceanic crust (AOC) from 5 ODP sites in the Eastern and Western Pacific Ocean. Crushing followed by heating experiments enabled determination of noble gases and halogens in fluid inclusions and mineral phases respectively. Except for He and Ar, Ne, Kr and Xe isotopic ratios were all air-like suggesting that primary MORB signatures have been completely overprinted by air and/or seawater interaction. In contrast, 3He/4He ratios obtained by crushing indicate that a mantle helium component is still preserved, and 40Ar/36Ar values are affected by radiogenic decay in the mineral phases. The 130Xe/36Ar and 84Kr/36Ar ratios are respectively up to 15 times and 5 times higher than those of seawater and the highest ratios are found in samples affected by low temperature alteration (shallower than 800-900 m sub-basement). We consider three possible processes: (i) adsorption onto the clays present in the samples; (ii) fluid inclusions with a marine pore fluid composition; and (iii) fractionation of seawater through phase separation caused by boiling. Ninety percent of the Cl, Br and I were released during the heating experiments, showing that halogens are dominantly held in mineral phases prior to subduction. I/Cl ratios vary by 4 orders of magnitude, from 3 × 10-6 to 2 × 10-2. The mean Br/Cl ratio is 30% lower than in MORB and seawater. I/Cl ratios lower than MORB values are attributed to Cl-rich amphibole formation caused by hydrothermal alteration at depths greater than 800-900 m sub-basement together with different extents of I loss during low and high temperature alteration. At shallower depths, I/Cl ratios higher than MORB values can be explained by the addition of organic-rich sediments or the presence of organic detritus, both known to efficiently sequester I. Concentrations of 36Ar of the pre-subducting materials are sufficient to account for the 36Ar and composition of the mantle in the context of existing subduction-flux models. We find the Cl subduction flux of the oceanic crust to be about three times higher than the previous estimates and that sufficient Cl and Br can potentially be delivered by subduction over the last 3 Ga to account for mantle source compositions.

Theoretical studies of ground and excited electronic States in a series of rhenium(i) bipyridine complexes containing diarylethynyl-based structure.

PubMed

Yang, Li; Ren, Ai-Min; Feng, Ji-Kang; Liu, Xiao-Dong; Ma, Yu-Guang; Zhang, Hong-Xing

2004-09-20

The photophysical properties, which vary as X is varied, of Re(I)-halide complexes (X2-bpy)ReICl(CO)3 (where X=ph, DAE, DNE, and DPE; ph = phenyl (1); DAE = di(amineoethynylbenzene) (2); DPE = di(phenylethynylbenzene) (3); DNE = di(nitroethynylbenzene) (4); bpy=2,2'bipyridine), are investigated using density functional theory (DFT). The electronic properties of the neutral molecules, in addition to the positive and negative ions, are studied using B3LYP functional. Excited singlet and triplet states are examined using time-dependent density functional theory (TDDFT). The low-lying excited-state geometries are optimized at the ab initio configuration interaction singlets level. As shown, the diarylethynyl-based structure is an integral component of the bpy pi-conjugated network, which results in a good planar structure. The occupied orbitals involved in the transitions have a significant mixture of metal Re and group Cl, and the lowest unoccupied orbital is a pi orbital, which extends from ligand bpy to diarylethynyl-based substituents. The luminescence for each complex originates from the lowest triplet excited states and is assigned to the mixing of MLCT and LLCT characters. Significant insights on the effects of these diarylethynyl conjugated structure and ending substituents (NH2, ph, and NO2) on absorption and emission spectra are observed by analysis of the results of the TDDFT method. The diarylethynyl-based pi-conjugated network makes both the absorption and emission spectra red-shifted compared with simple complex (bpy)ReICl(CO)3. Furthermore, an electron-releasing group (NH2) makes absorption and emission spectra blue-shift and an electron-withdrawing group (NO2) makes them red-shift. Copyright 2004 American Chemical Society

Coordination of the recruitment of the FANCD2 and PALB2 Fanconi anemia proteins by an ubiquitin signaling network.

PubMed

Bick, Gregory; Zhang, Fan; Meetei, A Ruhikanta; Andreassen, Paul R

2017-06-01

Fanconi anemia (FA) is a chromosome instability syndrome and the 20 identified FA proteins are organized into two main arms which are thought to function at distinct steps in the repair of DNA interstrand crosslinks (ICLs). These two arms include the upstream FA pathway, which culminates in the monoubiquitination of FANCD2 and FANCI, and downstream breast cancer (BRCA)-associated proteins that interact in protein complexes. How, and whether, these two groups of FA proteins are integrated is unclear. Here, we show that FANCD2 and PALB2, as indicators of the upstream and downstream arms, respectively, colocalize independently of each other in response to DNA damage induced by mitomycin C (MMC). We also show that ubiquitin chains are induced by MMC and colocalize with both FANCD2 and PALB2. Our finding that the RNF8 E3 ligase has a role in recruiting FANCD2 and PALB2 also provides support for the hypothesis that the two branches of the FA-BRCA pathway are coordinated by ubiquitin signaling. Interestingly, we find that the RNF8 partner, MDC1, as well as the ubiquitin-binding protein, RAP80, specifically recruit PALB2, while a different ubiquitin-binding protein, FAAP20, functions only in the recruitment of FANCD2. Thus, FANCD2 and PALB2 are not recruited in a single linear pathway, rather we define how their localization is coordinated and integrated by a network of ubiquitin-related proteins. We propose that such regulation may enable upstream and downstream FA proteins to act at distinct steps in the repair of ICLs.

REVEALING THE ACTIVATION PATHWAY FOR TMEM16A CHLORIDE CHANNELS FROM MACROSCOPIC CURRENTS AND KINETIC MODELS

PubMed Central

Contreras-Vite, Juan A.; Cruz-Rangel, Silvia; De Jesús-Pérez, José J.; Aréchiga Figueroa, Iván A.; Rodríguez-Menchaca, Aldo A.; Pérez-Cornejo, Patricia; Hartzell, H. Criss; Arreola, Jorge

2017-01-01

TMEM16A (ANO1), the pore-forming subunit of calcium-activated chloride channels, regulates several physiological and pathophysiological processes such as smooth muscle contraction, cardiac and neuronal excitability, salivary secretion, tumour growth, and cancer progression. Gating of TMEM16A is complex because it involves the interplay between increases in intracellular calcium concentration ([Ca2+]i), membrane depolarization, extracellular Cl− or permeant anions, and intracellular protons. Our goal here was to understand how these variables regulate TMEM16A gating and to explain four observations. a) TMEM16A is activated by voltage in the absence of intracellular Ca2+. b) The Cl− conductance is decreased after reducing extracellular Cl− concentration ([Cl−]o). c) ICl is regulated by physiological concentrations of [Cl−]o. d) In cells dialyzed with 0.2 µM [Ca2+]i, Cl− has a bimodal effect: at [Cl−]o < 30 mM TMEM16A current activates with a monoexponential time course, but above 30 mM [Cl−]o ICl activation displays fast and slow kinetics. To explain the contribution of Vm, Ca2+ and Cl− to gating, we developed a 12-state Markov chain model. This model explains TMEM16A activation as a sequential, direct, and Vm-dependent binding of two Ca2+ ions coupled to a Vm-dependent binding of an external Cl− ion, with Vm-dependent transitions between states. Our model predicts that extracellular Cl− does not alter the apparent Ca2+ affinity of TMEM16A, which we corroborated experimentally. Rather, extracellular Cl− acts by stabilizing the open configuration induced by Ca2+ and by contributing to the Vm dependence of activation. PMID:27138167

Compact TDLAS based optical sensor for ppb-level ethane detection by use of a 3.34 μm room-temperature CW interband cascade laser

DOE PAGES

Li, Chunguang; Dong, Lei; Zheng, Chuantao; ...

2016-03-26

A mid-infrared ethane (C 2H 6) sensor based on a wavelength modulation spectroscopy (WMS) technique was developed using a thermoelectrically cooled (TEC), continuous-wave (CW) interband cascade laser (ICL) emitting at 3.34 μm and a dense multi-pass gas cell (MPGC, 17 × 6.5 × 5.5 cm 3) with a 54.6 m optical path length. A compact optical sensor system with a physical size of 35.5 × 18 × 12.5 cm 3 was designed and constructed. An ICL was employed for targeting a strong C 2H 6 line at 2996.88 cm -1 at <100 Torr gas pressure in the fundamental absorption bandmore » of C 2H 6. The sensor performance, including the minimum detection limit (MDL) and the stability were improved by reducing the effect of laser power drift by means of the 2f/1f-WMS technique. A MDL of ~1.2 parts per billion (ppbv) for 2f-WMS and ~1.0 ppbv for 2f/1f-WMS were achieved, respectively, with a measurement time of 4 s. The MDL was further improved from 299 pptv (@108 s for 2f-WMS) to 239 pptv (@208 s for 2f/1f-WMS), based on an Allan deviation analysis.The rise time (@0 → 100 ppbv) and fall time (@100 → 0 ppbv) were determined to be ~64 s and ~48 s,respectively, at a gas pressure of <100 Torr for the C 2H 6 sensor operation.« less

Compact TDLAS based optical sensor for ppb-level ethane detection by use of a 3.34 μm room-temperature CW interband cascade laser

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Chunguang; Dong, Lei; Zheng, Chuantao

A mid-infrared ethane (C 2H 6) sensor based on a wavelength modulation spectroscopy (WMS) technique was developed using a thermoelectrically cooled (TEC), continuous-wave (CW) interband cascade laser (ICL) emitting at 3.34 μm and a dense multi-pass gas cell (MPGC, 17 × 6.5 × 5.5 cm 3) with a 54.6 m optical path length. A compact optical sensor system with a physical size of 35.5 × 18 × 12.5 cm 3 was designed and constructed. An ICL was employed for targeting a strong C 2H 6 line at 2996.88 cm -1 at <100 Torr gas pressure in the fundamental absorption bandmore » of C 2H 6. The sensor performance, including the minimum detection limit (MDL) and the stability were improved by reducing the effect of laser power drift by means of the 2f/1f-WMS technique. A MDL of ~1.2 parts per billion (ppbv) for 2f-WMS and ~1.0 ppbv for 2f/1f-WMS were achieved, respectively, with a measurement time of 4 s. The MDL was further improved from 299 pptv (@108 s for 2f-WMS) to 239 pptv (@208 s for 2f/1f-WMS), based on an Allan deviation analysis.The rise time (@0 → 100 ppbv) and fall time (@100 → 0 ppbv) were determined to be ~64 s and ~48 s,respectively, at a gas pressure of <100 Torr for the C 2H 6 sensor operation.« less

Enhanced photocatalytic activity of ternary CuInS2 nanocrystals synthesized from the combination of a binary Cu(I)S precursor and InCl3

NASA Astrophysics Data System (ADS)

Mondal, Gopinath; Santra, Ananyakumari; Jana, Sumanta; Pramanik, Nimai Chand; Mondal, Anup; Bera, Pulakesh

2018-04-01

Ternary copper indium sulfide (CIS) nanocrystals (NCs) have been synthesized by mixing of binary precursor [CuI(bdpa)2][CuICl2] ( 1) and/or [CuI(mdpa)2][CuICl2] ( 2) (where, mdpa and bdpa represent methyl and benzyl ester of 3,5-dimethyl pyrazole-1-dithioic acid, respectively) with InCl3 in a low-temperature solvothermal process. The +1 oxidation state of copper and the atomic ratio Cu to S (1:2) is atomically maintained in the pyrazole-based Cu(I)-S precursor to synthesize phase pure CuInS2. Coordinating solvents like ethylene diamine (EN) and ethylene glycol (EG) have been used in the synthesis without any surfactants. No use of external surfactants in the synthesis of CIS nanoparticles reveals that precursor acts as stabilizing agent. The synthesized nanocrystals were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and energy dispersive X-ray spectroscopy (EDX) studies. The optical property of the nanocrystals shows a pronounced quantum confinement effect in the particles with band gap energy ca. 1.5 eV. The formation mechanism of ternary CIS has been proposed. The pore size distributions of the particles show the average pore diameters 13.1 nm from 1 and 5.3 nm from 2. The calculated values of the specific surface area are 8.123 and 9.577 m2/g for 1 and 2, respectively. The excellent photocatalytic degradation of rose bengal (RB) and rhodamine B (RhB) was demonstrated by the porous CIS nanocrystals. [Figure not available: see fulltext.

The Average Star Formation Histories of Galaxies in Dark Matter Halos from z = 0-8

NASA Astrophysics Data System (ADS)

Behroozi, Peter S.; Wechsler, Risa H.; Conroy, Charlie

2013-06-01

We present a robust method to constrain average galaxy star formation rates (SFRs), star formation histories (SFHs), and the intracluster light (ICL) as a function of halo mass. Our results are consistent with observed galaxy stellar mass functions, specific star formation rates (SSFRs), and cosmic star formation rates (CSFRs) from z = 0 to z = 8. We consider the effects of a wide range of uncertainties on our results, including those affecting stellar masses, SFRs, and the halo mass function at the heart of our analysis. As they are relevant to our method, we also present new calibrations of the dark matter halo mass function, halo mass accretion histories, and halo-subhalo merger rates out to z = 8. We also provide new compilations of CSFRs and SSFRs; more recent measurements are now consistent with the buildup of the cosmic stellar mass density at all redshifts. Implications of our work include: halos near 1012 M ⊙ are the most efficient at forming stars at all redshifts, the baryon conversion efficiency of massive halos drops markedly after z ~ 2.5 (consistent with theories of cold-mode accretion), the ICL for massive galaxies is expected to be significant out to at least z ~ 1-1.5, and dwarf galaxies at low redshifts have higher stellar mass to halo mass ratios than previous expectations and form later than in most theoretical models. Finally, we provide new fitting formulae for SFHs that are more accurate than the standard declining tau model. Our approach places a wide variety of observations relating to the SFH of galaxies into a self-consistent framework based on the modern understanding of structure formation in ΛCDM. Constraints on the stellar mass-halo mass relationship and SFRs are available for download online.

High -- Resolution Laser Spectroscopy of the a 3Π1 ← X 1σ+ System of ICl in 0.7 μm Region.

NASA Astrophysics Data System (ADS)

Nishimiya, Nobuo; Yukiya, Tokio; Suzuki, Masao; Le Roy, Robert J.

2015-06-01

Spectroscopic data for the A 3Π1 and X 1σ+ states of I35/37Cl have been obtained by many researchers using grating spectrometers and Fourier-transform infrared spectrometers. In a previous paper we reported the measurement of doppler limited electronic vib-rotational absorption lines of the A 3Π1 ← X 1σ+ system of I35/37Cl using a source modulation method, and new Mass-reduced Dunham coefficients were reported for the X-state. However, it is becoming increasingly common to analyse diatomic molecule spectroscopic data using the ``direct-potential-fit'' (DPF) method in which observed transition energies are fitted to simulated spectra generated from analyic models for the potential energy function(s). This method tends to require fewer fitting parameters than traditional Dunham analyses, as well as having more robust extrapolation properties in both the v and J domains. The present work combines all available previously reported data for the A 3Π1 and X 1σ+ states with new measurements up to v'=10 in the 0.7μm region obtained with a tone burst method using a Ti:Sapphire Ring Laser (M Squared Ltd SolsTis CW with Tera scan) in the the first DPF analysis reported for this system. The results of this study and our new fully analytic potential energy functions for the A 3Π1 and X 1σ+ states of ICl will be presented. J.A. Coxon, R.M. Gordon and M.A. Wickramaaratchi, J. Mol. Spectr. 79 (1983) 363, 380. H. Hedderich P.F. Bernath and G.A. McRae J. Mol. Spectr. 155 (1992) 384. T.Yukiya, N. Nishimiya and M. Suzuki, J. Mol. Spectr. 269 (2011) 193.

HFF-DeepSpace Photometric Catalogs of the 12 Hubble Frontier Fields, Clusters, and Parallels: Photometry, Photometric Redshifts, and Stellar Masses

NASA Astrophysics Data System (ADS)

Shipley, Heath V.; Lange-Vagle, Daniel; Marchesini, Danilo; Brammer, Gabriel B.; Ferrarese, Laura; Stefanon, Mauro; Kado-Fong, Erin; Whitaker, Katherine E.; Oesch, Pascal A.; Feinstein, Adina D.; Labbé, Ivo; Lundgren, Britt; Martis, Nicholas; Muzzin, Adam; Nedkova, Kalina; Skelton, Rosalind; van der Wel, Arjen

2018-03-01

We present Hubble multi-wavelength photometric catalogs, including (up to) 17 filters with the Advanced Camera for Surveys and Wide Field Camera 3 from the ultra-violet to near-infrared for the Hubble Frontier Fields and associated parallels. We have constructed homogeneous photometric catalogs for all six clusters and their parallels. To further expand these data catalogs, we have added ultra-deep K S -band imaging at 2.2 μm from the Very Large Telescope HAWK-I and Keck-I MOSFIRE instruments. We also add post-cryogenic Spitzer imaging at 3.6 and 4.5 μm with the Infrared Array Camera (IRAC), as well as archival IRAC 5.8 and 8.0 μm imaging when available. We introduce the public release of the multi-wavelength (0.2–8 μm) photometric catalogs, and we describe the unique steps applied for the construction of these catalogs. Particular emphasis is given to the source detection band, the contamination of light from the bright cluster galaxies (bCGs), and intra-cluster light (ICL). In addition to the photometric catalogs, we provide catalogs of photometric redshifts and stellar population properties. Furthermore, this includes all the images used in the construction of the catalogs, including the combined models of bCGs and ICL, the residual images, segmentation maps, and more. These catalogs are a robust data set of the Hubble Frontier Fields and will be an important aid in designing future surveys, as well as planning follow-up programs with current and future observatories to answer key questions remaining about first light, reionization, the assembly of galaxies, and many more topics, most notably by identifying high-redshift sources to target.

Acetaldehyde Stimulates FANCD2 Monoubiquitination, H2AX Phosphorylation, and BRCA1 Phosphorylation in Human Cells in Vitro: Implications for Alcohol-Related Carcinogenesis

PubMed Central

Marietta, Cheryl; Thompson, Larry H.; Lamerdin, Jane E.; Brooks, P.J.

2009-01-01

According to a recent IARC Working Group report, alcohol consumption is causally related to an increased risk of cancer of the upper aerodigestive tract, liver, colorectum, and female breast (Lancet Oncol. 2007 8:292–3). Several lines of evidence indicate that acetaldehyde (AA), the first product of alcohol metabolism, plays a very important role in alcohol-related carcinogenesis, particularly in the esophagus. We previously proposed a model for alcohol-related carcinogenesis in which AA, generated from alcohol metabolism, reacts in cells to generate DNA lesions that form interstrand crosslinks (ICLs) (Nucleic Acids Res. 2005 33:3513–20). Since the Fanconi anemia-breast cancer associated (FANC-BRCA) DNA damage response network plays a crucial role in protecting cells against ICLs, in the present work we tested this hypothesis by exposing cells to AA and monitoring activation of this network. We found that AA exposure results in a concentration-dependent increase in FANCD2 monoubiquitination, which is dependent upon the FANC core complex. AA also stimulated BRCA1 phosphorylation at Ser1524 and increased the level of γH2AX, with both modifications occurring in a dose-dependent manner. However, AA did not detectably increase the levels of hyperphosphorylated RPA34, a marker of single-stranded DNA exposure at replication forks. These results provide the initial description of the AA-DNA damage response, which is qualitatively similar to the cellular response to mitomycin C, a known DNA crosslinking agent. We discuss the mechanistic implications of these results, as well as their possible relationship to alcohol-related carcinogenesis in different human tissues. PMID:19428384

Loss of CHK1 function impedes DNA damage-induced FANCD2 monoubiquitination but normalizes the abnormal G2 arrest in Fanconi anemia.

PubMed

Guervilly, Jean-Hugues; Macé-Aimé, Gaëtane; Rosselli, Filippo

2008-03-01

Fanconi anemia (FA) is a cancer-prone hereditary disease resulting from mutations in one of the 13 genes defining the FANC/BRCA pathway. This pathway is involved in the cellular resistance to DNA-cross-linking agents. How the FANC/BRCA pathway is activated and why its deficiency leads to the accumulation of FA cells with a 4N DNA content are still poorly answered questions. We investigated the involvement of ATR pathway members in these processes. We show here that RAD9 and RAD17 are required for DNA interstrand cross-link (ICL) resistance and for the optimal activation of FANCD2. Moreover, we demonstrate that CHK1 and its interacting partner CLASPIN that act downstream in the ATR pathway are required for both FANCD2 monoubiquitination and assembling in subnuclear foci in response to DNA damage. Paradoxically, in the absence of any genotoxic stress, CHK1 or CLASPIN depletion results in an increased basal level of FANCD2 monoubiquitination and focalization. We also demonstrate that the ICL-induced accumulation of FA cells in late S/G2 phase is dependent on ATR and CHK1. In agreement with this, CHK1 phosphorylation is enhanced in FA cells, and chemical inhibition of the ATR/CHK1 axis in FA lymphoblasts decreases their sensitivity to mitomycin C. In conclusion, this work describes a complex crosstalk between CHK1 and the FANC/BRCA pathway: CHK1 activates this pathway through FANCD2 monoubiquitination, whereas FA deficiency leads to a CHK1-dependent G2 accumulation, raising the possibility that the FANC/BRCA pathway downregulates CHK1 activation.

A Study of the Toxicity of the Metabolites of the Cruise Missile Fuel JP-10 on Several Animal Species.

DTIC Science & Technology

1986-09-30

AD-A174 758 A STUDY OF THE TOXICITY OF THE NETABOLITES OF THE t/1 CRUISE MISSILE FUEL JP- (U) WRIGHT STATE UNIV DAYTON OHIO M P SERVE 38 SEP 86 WSU...rri P.-d n- i approved po’ i.’ ! v I,,AF:R 19 ,)-12. KA TTHEW J. Chief, Techl-icl Informt ion Division A STUDY OF THE TOXICITY OF TH4E METABOLITES OF...Security Class, fcation)IrC A study of the toxicity of the --tim..... f 0.01. metabolites of the cruise missle fuel JP-10 on several animal species. 12

Assessment of Potential for Colloidal Fuels

DTIC Science & Technology

1975-06-01

Scientific Officer U casfe ""DOffice of Naval ResearchS800O N, Quinc’y $truet -~~~~~_ ! A r i g o , V C1 ) V ; I - A S S I F I C A T J "O Nr D f J...of Colloidal Fuels .............. . . page 12 The BCL Colloidal Fuel Costing Rationale . . . . . . . Appendix A $ Alternative Assessment of the Cost...partievia ny as coal part icl siz(-s are reducud it’ss than 70 microns. Note in Table 11 that the impact of thev fine~r Coal Of Batch1 12 rc suIt’s in a moiC

Soil, water, and nutrient losses from management alternatives for degraded pasture in Brazilian Atlantic Rainforest biome.

PubMed

Rocha Junior, Paulo Roberto da; Andrade, Felipe Vaz; Mendonça, Eduardo de Sá; Donagemma, Guilherme Kangussú; Fernandes, Raphael Bragança Alves; Bhattharai, Rabin; Kalita, Prasanta Kumar

2017-04-01

The objective of this study was to evaluate sediment, water and nutrient losses from different pasture managements in the Atlantic Rainforest biome. A field study was carried out in Alegre Espiríto Santo, Brazil, on a Xanthic Ferralsol cultivated with braquiaria (Brachiaria brizantha). The six pasture managements studied were: control (CON), chisel (CHI), fertilizer (FER), burned (BUR), plowing and harrowing (PH), and integrated crop-livestock (iCL). Runoff and sediment samples were collected and analyzed for calcium (Ca), magnesium (Mg), potassium (K), phosphorus (P) and organic carbon contents. Soil physical attributes and above and below biomass were also evaluated. The results indicated that higher water loss was observed for iCL (129.90mm) and CON (123.25mm) managements, and the sediment losses were higher for CON (10.24tha -1 ) and BUR (5.20tha -1 ) managements when compared to the other managements. Majority of the nutrients losses occurred in dissolved fraction (99% of Ca, 99% of Mg, 96% of K, and 65% of P), whereas a significant fraction of organic carbon (80%) loss occurred in a particulate form. Except for P, other nutrients (Ca, Mg and K) and organic carbon losses were higher in coarse sediment compared to fine sediment. The greater losses of sediment, organic carbon, and nutrients were observed for CON followed by BUR management (p<0.05). Our findings indicated that the traditional pasture management adopted in the Atlantic Rainforest needs to be rethought and burned management should be avoided. Based on the water, soil, and nutrient losses from various practices, to reduce pasture degradation, farmers should adopt edaphic practices by applying lime and fertilize to improve pasture growth and soil cover, and reducing soil erosion in the hilly Brazilian Atlantic Rainforest biome. Copyright © 2016. Published by Elsevier B.V.

Anoctamin 6 Contributes to Cl− Secretion in Accessory Cholera Enterotoxin (Ace)-stimulated Diarrhea

PubMed Central

Aoun, Joydeep; Hayashi, Mikio; Sheikh, Irshad Ali; Sarkar, Paramita; Saha, Tultul; Ghosh, Priyanka; Bhowmick, Rajsekhar; Ghosh, Dipanjan; Chatterjee, Tanaya; Chakrabarti, Pinak; Chakrabarti, Manoj K.; Hoque, Kazi Mirajul

2016-01-01

Accessory cholera enterotoxin (Ace) of Vibrio cholerae has been shown to contribute to diarrhea. However, the signaling mechanism and specific type of Cl− channel activated by Ace are still unknown. We have shown here that the recombinant Ace protein induced ICl of apical plasma membrane, which was inhibited by classical CaCC blockers. Surprisingly, an Ace-elicited rise of current was neither affected by ANO1 (TMEM16A)-specific inhibitor T16A(inh)-AO1(TAO1) nor by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker, CFTR inh-172. Ace stimulated whole-cell current in Caco-2 cells. However, the apical ICl was attenuated by knockdown of ANO6 (TMEM16F). This impaired phenotype was restored by re-expression of ANO6 in Caco-2 cells. Whole-cell patch clamp recordings of ANO currents in HEK293 cells transiently expressing mouse ANO1-mCherry or ANO6-GFP confirmed that Ace induced Cl− secretion. Application of Ace produced ANO6 but not the ANO1 currents. Ace was not able to induce a [Ca2+]i rise in Caco-2 cells, but cellular abundance of phosphatidylinositol 4,5-bisphosphate (PIP2) increased. Identification of the PIP2-binding motif at the N-terminal sequence among human and mouse ANO6 variants along with binding of PIP2 directly to ANO6 in HEK293 cells indicate likely PIP2 regulation of ANO6. The biophysical and pharmacological properties of Ace stimulated Cl− current along with intestinal fluid accumulation, and binding of PIP2 to the proximal KR motif of channel proteins, whose mutagenesis correlates with altered binding of PIP2, is comparable with ANO6 stimulation. We conclude that ANO6 is predominantly expressed in intestinal epithelia, where it contributes secretory diarrhea by Ace stimulation in a calcium-independent mechanism of RhoA-ROCK-PIP2 signaling. PMID:27799301

Ubiquitylation and the Fanconi Anemia Pathway

PubMed Central

Garner, Elizabeth; Smogorzewska, Agata

2012-01-01

The Fanconi anemia (FA) pathway maintains genome stability through co-ordination of DNA repair of interstrand crosslinks (ICLs). Disruption of the FA pathway yields hypersensitivity to interstrand crosslinking agents, bone marrow failure and cancer predisposition. Early steps in DNA damage dependent activation of the pathway are governed by monoubiquitylation of FANCD2 and FANCI by the intrinsic FA E3 ubiquitin ligase, FANCL. Downstream FA pathway components and associated factors such as FAN1 and SLX4 exhibit ubiquitin-binding motifs that are important for their DNA repair function, underscoring the importance of ubiquitylation in FA pathway mediated repair. Importantly, ubiquitylation provides the foundations for cross-talk between repair pathways, which in concert with the FA pathway, resolve interstrand crosslink damage and maintain genomic stability. PMID:21605559

Exploring the High Energy Universe: GLAST Mission and Science

NASA Technical Reports Server (NTRS)

McEnery, Julie

2007-01-01

GLAST, the Gamma-Ray Large Area Space Telescope, is NASA's next-generation high-energy gamma-ray satellite scheduled for launch in Autumn 2007. GLAST will allow measurements of cosmic gamma-ray sources in t he 10 MeV to 100 GeV energy band to be made with unprecedented sensi tivity. Amongst its key scientific objectives are to understand part icle acceleration in Active Galactic Nuclei, Pulsars and Supernovae Remnants, to provide high resolution measurements of unidentified ga mma-ray sources, to study transient high energy emission from objects such as gamma-ray bursts, and to probe Dark Matter and the early Uni verse. Dr. McEnery will present an overview of the GLAST mission and its scientific goals.

Energy Efficient Engine acoustic supporting technology report

NASA Technical Reports Server (NTRS)

Lavin, S. P.; Ho, P. Y.

1985-01-01

The acoustic development of the Energy Efficient Engine combined testing and analysis using scale model rigs and an integrated Core/Low Spool demonstration engine. The scale model tests show that a cut-on blade/vane ratio fan with a large spacing (S/C = 2.3) is as quiet as a cut-off blade/vane ratio with a tighter spacing (S/C = 1.27). Scale model mixer tests show that separate flow nozzles are the noisiest, conic nozzles the quietest, with forced mixers in between. Based on projections of ICLS data the Energy Efficient Engine (E3) has FAR 36 margins of 3.7 EPNdB at approach, 4.5 EPNdB at full power takeoff, and 7.2 EPNdB at sideline conditions.

Bus current analysis of high power cryocooler's controller

NASA Astrophysics Data System (ADS)

Jin, Zhanlei; Sun, Qiyang; Dai, Liqun; Dong, Jie

2016-03-01

Current analysis was an important research content for reducing power of cryocooler's controller. Simulation was done among load current, H bridge current and power current refer to 42V bus power voltage. Then relationship among IL1, IC1, ρ and IM1 was established. Simulation results indicate that IL1-max, IL1-ave, IL1-rms, IC1-min and IC1-ave were linearly increasing to ρ and IM1, especially IL1-rms ≈ 0.612ρ IM1-max . IC1-rms increase firstly then decrease with the increasing of ρ. IC1-rms reaches maximum when ρ=0.8, then ICL-rms =(12.32/RM1 + 0.98) exp -((ρ-0.78)/0.57)2. The results were useful for miniaturizing cryocooler's controller.

Reaction to Halogens and Interhalogens with 4-Halo-1,1,2-trifluorobut-1-enes: Rearrangement of 3-Membered Halonium to 5-Membered Trifluorotetramethylene Halonium Ion Intermediates and Comparison of Open-Chloronium Fluorosubstituted Ions to Flurocarbocations from Protons (Preprint)

DTIC Science & Technology

2008-02-28

were found to be open-ion (A or E), unsymmetrical (B or D), or symmetrical C depending on the halogen electrophile and on the position and number of...Rearranged products 4 (Structures A-E) 1 Z = Cl 2 Z = Br 3 Z = I XY = Cl2, Br2, BrCl ICl, IBr Scheme 1 Y on the fluorine atoms of 5 shield the carbon nucleus...and 3) WITH HALOGEN ELECTROPHILES IN METHYLENE CHLORIDE F F F Z XY CH2Cl2 CF2CFZ Y X CF2CFZ X Y CF2CFY X Z + + M aM Rearranged Run Alkene (Z

Influence of repetitive UVA stimulation on skin protection capacity and antioxidant efficacy.

PubMed

Rohr, Mathias; Rieger, Ingrid; Jain, Anil; Schrader, Andreas

2011-01-01

Topically applied antioxidants (AOs) are widely used in cosmetic products - especially in day and sun care - to help reduce oxidative stress caused by exogenous influences such as ultraviolet (UV) radiation. Despite several advances in recent years, little is known about the duration of protective effects by application of topical AOs, AO protection capacity (APC) or the activation of an endogenous protection capacity (EPC). By measuring oxidative-stress-induced photon emission of human skin in vivo with the ICL-S method (induced chemiluminescence of human skin), the protective effect of daily AO treatment for 2 weeks was examined on 4 consecutive days after treatment. UVA-dose-independent effects were investigated by decay curve intersection point analysis. In addition, chemiluminescence signal integration was used to investigate the influence of different UVA doses for stimulation on the determined APC as well as the modulation of the EPC by repetitive UVA stimulation both forming the skin protection capacity (SPC). The SPC showed a strong dependency on the UVA dose used for stimulation. AO pretreatment was more effective against lower UVA doses. Over the course of 4 days, the AO-induced SPC did not change significantly for a given UVA dose. Analyzing the decay curve intersection point for 2 different UVA doses, however, revealed a decrease in SPC with time. In addition, we found that a repetitive UVA irradiation of 1 J/cm(2) caused a statistically significant protective effect against UVA irradiation by stimulation of endogenous mechanisms. Topically supplemented AOs provide a protective effect against oxidative stress for at least 3 days, supporting their widespread use in cosmetic products. Especially their interaction with cutaneous protective mechanisms should be investigated in more detail for maximal protection, as endogenous defense mechanisms are already triggered by 2 low-dose UVA irradiations within 24 h. In summary, the in vivo measurement of UVA-induced cutaneous chemiluminescence permits the UVA-dose-independent determination of the AO efficacy for better comparability of the results while also taking endogenous defense mechanisms into account. Copyright © 2011 S. Karger AG, Basel.

Insilico study of the A(2A)R-D (2)R kinetics and interfacial contact surface for heteromerization.

PubMed

Prakash, Amresh; Luthra, Pratibha Mehta

2012-10-01

G-protein-coupled receptors (GPCRs) are cell surface receptors. The dynamic property of receptor-receptor interactions in GPCRs modulates the kinetics of G-protein signaling and stability. In the present work, the structural and dynamic study of A(2A)R-D(2)R interactions was carried to acquire the understanding of the A(2A)R-D(2)R receptor activation and deactivation process, facilitating the design of novel drugs and therapeutic target for Parkinson's disease. The structure-based features (Alpha, Beta, SurfAlpha, and SurfBeta; GapIndex, Leakiness and Gap Volume) and slow mode model (ENM) facilitated the prediction of kinetics (K (off), K (on), and K (d)) of A(2A)R-D(2)R interactions. The results demonstrated the correlation coefficient 0.294 for K (d) and K (on) and the correlation coefficient 0.635 for K (d) and K (off), and indicated stable interfacial contacts in the formation of heterodimer. The coulombic interaction involving the C-terminal tails of the A(2A)R and intracellular loops (ICLs) of D(2)R led to the formation of interfacial contacts between A(2A)R-D(2)R. The properties of structural dynamics, ENM and KFC server-based hot-spot analysis illustrated the stoichiometry of A(2A)R-D(2)R contact interfaces as dimer. The propensity of amino acid residues involved in A(2A)R-D(2)R interaction revealed the presence of positively (R, H and K) and negatively (E and D) charged structural motif of TMs and ICL3 of A(2A)R and D(2)R at interface of dimer contact. Essentially, in silico structural and dynamic study of A(2A)R-D(2)R interactions will provide the basic understanding of the A(2A)R-D(2)R interfacial contact surface for activation and deactivation processes, and could be used as constructive model to recognize the protein-protein interactions in receptor assimilations.

Can short-term pasture management increase C balance in the Atlantic Rainforest?

PubMed

da Rocha Junior, Paulo Roberto; Andrade, Felipe Vaz; Santos Satiro, Lucas; Donagemma, Guilherme Kangussú; de Sá Mendonça, Eduardo

2018-05-11

Few studies have shown the importance of different pasture management practices on C storage and the reduction of CO 2 -C emissions in tropical conditions. The objective of the present study was to determine short-term changes in C pools and C balance from different pasture management practices established in the Atlantic Rainforest. A field study was carried out in Alegre, ES, Brazil from September 2013 to August 2014 to investigate the first-year effect of pasture management practices on a Udult clayey soil. The different pasture management practices studied included the following: control (CON), chiseled (CHI), fertilized (FER), burned (BUR), integrated with crop-livestock (iCL) systems, and plowed and harrowed (PH). Monthly disturbed and undisturbed soil samples were taken at two different layers (0.00-0.05 and 0.05-0.20 m) for chemical, physical, and organic matter characterization. C inputs monitored in aboveground pools included plant aerial parts and litter, and belowground pools included roots and soil C stocks. C outputs monitored were CO 2 -C emissions, erosion water, and sediment. C balance was considered the difference between inputs and outputs in each treatment during four seasons. The spring and summer seasons had a strong influence on C inputs and outputs where there is significant difference between spring and summer, while the autumn and winter seasons had less influence. All pasture management practices exhibited positive C balance after 1 year. High values of C balance were verified in pastures fertilized (FER) (53.04 Mg ha -1  year -1 . Intermediate C balance was found in the burned (BUR) (40.84 Mg ha -1  year -1 ), traditional control (CON) (40.31 Mg ha -1  year -1 ), and in the plowing and harrowing (PH) (40.02 Mg ha -1  year -1 ) management practices. The practices of chiseled (40.00 Mg ha -1  year -1 ) and integrated crop-livestock systems (iCL) (59.06 Mg ha -1  year -1 ) resulted in low C balance.

Operational strategies, monitoring and control of heterologous protein production in the methylotrophic yeast Pichia pastoris under different promoters: A review

PubMed Central

Cos, Oriol; Ramón, Ramón; Montesinos, José Luis; Valero, Francisco

2006-01-01

The methylotrophic yeast Pichia pastoris has been widely reported as a suitable expression system for heterologous protein production. The use of different phenotypes under PAOX promoter, other alternative promoters, culture medium, and operational strategies with the objective to maximize either yield or productivity of the heterologous protein, but also to obtain a repetitive product batch to batch to get a robust process for the final industrial application have been reported. Medium composition, kinetics growth, fermentation operational strategies from fed-batch to continuous cultures using different phenotypes with the most common PAOX promoter and other novel promoters (GAP, FLD, ICL), the use of mixed substrates, on-line monitoring of the key fermentation parameters (methanol) and control algorithms applied to the bioprocess are reviewed and discussed in detail. PMID:16600031

Long-term experience with deferasirox (ICL670), a once-daily oral iron chelator, in the treatment of transfusional iron overload.

PubMed

Cappellini, M D; Taher, A

2008-09-01

Chronic iron overload from frequent blood transfusions to treat patients with severe anaemias leads to significant morbidity and mortality. While deferoxamine, the current standard of care, is an effective iron chelator, it requires subcutaneous infusion for 8-12 h/day, 5-7 days/week. This regimen is problematic and impacts significantly on patients' daily life. To evaluate the efficacy and tolerability of deferasirox, a once-daily oral iron chelator. To review the available data reported in peer-reviewed journals (using PubMed) and at medical conferences. Deferasirox is effective in reducing or maintaining iron burden in patients with transfusion-dependent anaemias. As deferasirox is orally administered, the inconvenience of parenteral administration with deferasirox is avoided. Deferasirox improves patient satisfaction and is expected to improve compliance with iron chelation therapy.

Synthesis of G-N2-(CH2)3-N2-G Trimethylene DNA interstrand cross-links

PubMed Central

Gruppi, Francesca; Salyard, Tracy L. Johnson; Rizzo, Carmelo J.

2014-01-01

The synthesis of G-N2-(CH2)3-N2-G trimethylene DNA interstrand cross-links (ICLs) in a 5′-CG-3′ and 5′-GC-3′ sequence from oligodeoxynucleotides containing N2-(3-aminopropyl)-2′-deoxyguanosine and 2-fluoro-O6-(trimethylsilylethyl)inosine is presented. Automated solid-phase DNA synthesis was used for unmodified bases and modified nucleotides were incorporated via their corresponding phosphoramidite reagent by a manual coupling protocol. The preparation of the phosphoramidite reagents for incorporation of N2-(3-aminopropyl)-2′-deoxyguanosine is reported. The high-purity trimethylene DNA interstrand cross-link product is obtained through a nucleophilic aromatic substitution reaction between the N2-(3-aminopropyl)-2′-deoxyguanosine and 2-fluoro-O6-(trimethylsilylethyl)inosine containing oligodeoxynucleotides. PMID:25431636

Correction of anemia in a transfusion-dependent patient with primary myelofibrosis receiving iron chelation therapy with deferasirox (Exjade®, ICL670)

PubMed Central

Di Tucci, Anna Angela; Murru, Roberta; Alberti, Daniele; Rabault, Bertrand; Deplano, Simona; Angelucci, Emanuele

2007-01-01

Transfusional iron overload in patients with chronic anemias can result in multiple organ failure. Experience in the management of iron overload in patients with myelodysplastic syndromes is limited, as many do not receive chelation therapy due to short-life expectancy and the difficulties associated with the administration of the current reference standard chelator, deferoxamine. There have, however, been some reports of reduced transfusion requirement associated with chelation therapy in patients with myelodysplastic syndromes and myelofibrosis. Here, we discuss a patient with primary myelofibrosis and related transfusion-dependent anemia who received chelation therapy with the once-daily oral iron chelator, deferasirox. In addition to the reduced iron levels, the patient demonstrated an unexpected reduction in blood transfusion requirement, ultimately resulting in long-lasting transfusion-free survival. PMID:17391307

KAPPA -- Kernel Application Package

NASA Astrophysics Data System (ADS)

Currie, Malcolm J.; Berry, David. S.

KAPPA is an applications package comprising about 180 general-purpose commands for image processing, data visualisation, and manipulation of the standard Starlink data format---the NDF. It is intended to work in conjunction with Starlink's various specialised packages. In addition to the NDF, KAPPA can also process data in other formats by using the `on-the-fly' conversion scheme. Many commands can process data arrays of arbitrary dimension, and others work on both spectra and images. KAPPA operates from both the UNIX C-shell and the ICL command language. This document describes how to use KAPPA and its features. There is some description of techniques too, including a section on writing scripts. This document includes several tutorials and is illustrated with numerous examples. The bulk of this document comprises detailed descriptions of each command as well as classified and alphabetical summaries.

A switched systems approach to image-based estimation

NASA Astrophysics Data System (ADS)

Parikh, Anup

With the advent of technological improvements in imaging systems and computational resources, as well as the development of image-based reconstruction techniques, it is necessary to understand algorithm performance when subject to real world conditions. Specifically, this dissertation focuses on the stability and performance of a class of image-based observers in the presence of intermittent measurements, caused by e.g., occlusions, limited FOV, feature tracking losses, communication losses, or finite frame rates. Observers or filters that are exponentially stable under persistent observability may have unbounded error growth during intermittent sensing, even while providing seemingly accurate state estimates. In Chapter 3, dwell time conditions are developed to guarantee state estimation error convergence to an ultimate bound for a class of observers while undergoing measurement loss. Bounds are developed on the unstable growth of the estimation errors during the periods when the object being tracked is not visible. A Lyapunov-based analysis for the switched system is performed to develop an inequality in terms of the duration of time the observer can view the moving object and the duration of time the object is out of the field of view. In Chapter 4, a motion model is used to predict the evolution of the states of the system while the object is not visible. This reduces the growth rate of the bounding function to an exponential and enables the use of traditional switched systems Lyapunov analysis techniques. The stability analysis results in an average dwell time condition to guarantee state error convergence with a known decay rate. In comparison with the results in Chapter 3, the estimation errors converge to zero rather than a ball, with relaxed switching conditions, at the cost of requiring additional information about the motion of the feature. In some applications, a motion model of the object may not be available. Numerous adaptive techniques have been developed to compensate for unknown parameters or functions in system dynamics; however, persistent excitation (PE) conditions are typically required to ensure parameter convergence, i.e., learning. Since the motion model is needed in the predictor, model learning is desired; however, PE is difficult to insure a priori and infeasible to check online for nonlinear systems. Concurrent learning (CL) techniques have been developed to use recorded data and a relaxed excitation condition to ensure convergence. In CL, excitation is only required for a finite period of time, and the recorded data can be checked to determine if it is sufficiently rich. However, traditional CL requires knowledge of state derivatives, which are typically not measured and require extensive filter design and tuning to develop satisfactory estimates. In Chapter 5 of this dissertation, a novel formulation of CL is developed in terms of an integral (ICL), removing the need to estimate state derivatives while preserving parameter convergence properties. Using ICL, an estimator is developed in Chapter 6 for simultaneously estimating the pose of an object as well as learning a model of its motion for use in a predictor when the object is not visible. A switched systems analysis is provided to demonstrate the stability of the estimation and prediction with learning scheme. Dwell time conditions as well as excitation conditions are developed to ensure estimation errors converge to an arbitrarily small bound. Experimental results are provided to illustrate the performance of each of the developed estimation schemes. The dissertation concludes with a discussion of the contributions and limitations of the developed techniques, as well as avenues for future extensions.

Highly Productive Application Development with ViennaCL for Accelerators

NASA Astrophysics Data System (ADS)

Rupp, K.; Weinbub, J.; Rudolf, F.

2012-12-01

The use of graphics processing units (GPUs) for the acceleration of general purpose computations has become very attractive over the last years, and accelerators based on many integrated CPU cores are about to hit the market. However, there are discussions about the benefit of GPU computing when comparing the reduction of execution times with the increased development effort [1]. To counter these concerns, our open-source linear algebra library ViennaCL [2,3] uses modern programming techniques such as generic programming in order to provide a convenient access layer for accelerator and GPU computing. Other GPU-accelerated libraries are primarily tuned for performance, but less tailored to productivity and portability: MAGMA [4] provides dense linear algebra operations via a LAPACK-comparable interface, but no dedicated matrix and vector types. Cusp [5] is closest in functionality to ViennaCL for sparse matrices, but is based on CUDA and thus restricted to devices from NVIDIA. However, no convenience layer for dense linear algebra is provided with Cusp. ViennaCL is written in C++ and uses OpenCL to access the resources of accelerators, GPUs and multi-core CPUs in a unified way. On the one hand, the library provides iterative solvers from the family of Krylov methods, including various preconditioners, for the solution of linear systems typically obtained from the discretization of partial differential equations. On the other hand, dense linear algebra operations are supported, including algorithms such as QR factorization and singular value decomposition. The user application interface of ViennaCL is compatible to uBLAS [6], which is part of the peer-reviewed Boost C++ libraries [7]. This allows to port existing applications based on uBLAS with a minimum of effort to ViennaCL. Conversely, the interface compatibility allows to use the iterative solvers from ViennaCL with uBLAS types directly, thus enabling code reuse beyond CPU-GPU boundaries. Out-of-the-box support for types from the Eigen library [8] and MTL 4 [9] are provided as well, enabling a seamless transition from single-core CPU to GPU and multi-core CPU computations. Case studies from the numerical solution of PDEs are given and isolated performance benchmarks are discussed. Also, pitfalls in scientific computing with GPUs and accelerators are addressed, allowing for a first evaluation of whether these novel devices can be mapped well to certain applications. References: [1] R. Bordawekar et al., Technical Report, IBM, 2010 [2] ViennaCL library. Online: http://viennacl.sourceforge.net/ [3] K. Rupp et al., GPUScA, 2010 [4] MAGMA library. Online: http://icl.cs.utk.edu/magma/ [5] Cusp library. Online: http://code.google.com/p/cusp-library/ [6] uBLAS library. Online: http://www.boost.org/libs/numeric/ublas/ [7] Boost C++ Libraries. Online: http://www.boost.org/ [8] Eigen library. Online: http://eigen.tuxfamily.org/ [9] MTL 4 Library. Online: http://www.mtl4.org/

Diagnosis of Fanconi Anemia by Diepoxybutane Analysis

PubMed Central

Auerbach, Arleen D.

2015-01-01

Fanconi anemia (FA) is a genetically and phenotypically heterogeneous disorder characterized by congenital malformations, progressive bone marrow failure, and predisposition to cancer, particularly hematological malignancies and solid tumors of the head and neck. The main role of FA proteins is in the repair of DNA interstrand crosslinks (ICLs). FA results from pathogenic variants in at least 16 distinct genes, causing genomic instability. Although the highly variable phenotype makes accurate diagnosis on the basis of clinical manifestations difficult in some patients, diagnosis based on a profound sensitivity to DNA crosslinking agents can be used to identify the pre-anemia patient as well as patients with aplastic anemia or leukemia who may or may not have the physical stigmata associated with the syndrome. Diepoxybutane (DEB) analysis is the preferred test for FA because other agents have higher rates of false-positive and false-negative results. PMID:25827349

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Lei; Yu, Yajun; Li, Chunguang

A ppb-level formaldehyde (H 2CO) sensor was developed using a thermoelectrically cooled (TEC), continuous-wave (CW) room temperature interband cascade laser (ICL) emitting at 3.59 μm and a miniature dense pattern multipass gas cell with >50 m optical path length. Performance of the sensor was investigated with two measurement schemes: direct absorption (DAS) and wavelength modulation spectroscopy (WMS). With an integration time of less than 1.5 second, a detection limit of ~3 ppbv for H 2CO measurement with precision of 1.25 ppbv for DAS and 0.58 ppbv for WMS, respectively, was achieved without zero air based background subtraction. An Allan-Werle variancemore » analysis indicated that the precisions can be further improved to 0.26 ppbv @ 300s for DAS and 69 pptv @ 90 s for WMS, respectively. Finally, a side-by-side comparison between two measurement schemes is also discussed in detail.« less

Exploration of freely available web-interfaces for comparative homology modelling of microbial proteins.

PubMed

Nema, Vijay; Pal, Sudhir Kumar

2013-01-01

This study was conducted to find the best suited freely available software for modelling of proteins by taking a few sample proteins. The proteins used were small to big in size with available crystal structures for the purpose of benchmarking. Key players like Phyre2, Swiss-Model, CPHmodels-3.0, Homer, (PS)2, (PS)(2)-V(2), Modweb were used for the comparison and model generation. Benchmarking process was done for four proteins, Icl, InhA, and KatG of Mycobacterium tuberculosis and RpoB of Thermus Thermophilus to get the most suited software. Parameters compared during analysis gave relatively better values for Phyre2 and Swiss-Model. This comparative study gave the information that Phyre2 and Swiss-Model make good models of small and large proteins as compared to other screened software. Other software was also good but is often not very efficient in providing full-length and properly folded structure.

Prediction of the average skin temperature in warm and hot environments.

PubMed

Mehnert, P; Malchaire, J; Kampmann, B; Piette, A; Griefahn, B; Gebhardt, H

2000-05-01

The prediction of the mean skin temperature used for the Required Sweat Rate index was criticised for not being valid in conditions with high radiation and high humidity. Based on a large database provided by 9 institutes, 1999 data points obtained using steady-state conditions, from 1399 experiments and involving 377 male subjects, were used for the development of a new prediction model. The observed mean skin temperatures ranged from 30.7 degrees C to 38.6 degrees C. Experimental conditions included air temperatures (Ta) between 20 and 55 degrees C, mean radiant temperatures (Tr) up to 145 degrees C, partial vapour pressures (Pa) from 0.2 to 5.3 kPa, air velocities (v(a)) between 0.1 and 2 m/s, and metabolic rates (M) from 102 to 620 W. Rectal temperature (T(re)) was included in the models to increase the accuracy of prediction. Separate models were derived for nude (clothing insulation, I(cl), < or = 0.2 clo, where 1 clo = 0.155 m2 x degrees C x W(-1), which is equivalent to the thermal insulation of clothing necessary to maintain a resting subject in comfort in a normally ventilated room, air movement = 10 cm/s, at a temperature of 21 degrees C and a humidity of less than 50%) and clothed (0.6 < or = I(cl) < or = 1.0 clo) subjects using a multiple linear regression technique with re-sampling (non-parametric bootstrap). The following expressions were obtained for nude and clothed subjects, respectively: T(sk) = 7.19 + 0.064Ta + 0.061Tr + 0.198Pa - 0.348v(a) + 0.616T(re) and T(sk) = 12.17 + 0.020Ta + 0.044Tr + 0.194Pa - 0.253v(a) + 0.0029M + 0.513T(re). For the nude and clothed subjects, 83.3% and 81.8%, respectively, of the predicted skin temperatures were within the range of +/- 1 degree C of the observed skin temperatures. It is concluded that the proposed models for the prediction of the mean skin temperature are valid for a wide range of warm and hot ambient conditions in steady-state conditions, including those of high radiation and high humidity.

Sedimentary halogens and noble gases within Western Antarctic xenoliths: Implications of extensive volatile recycling to the sub continental lithospheric mantle

NASA Astrophysics Data System (ADS)

Broadley, Michael W.; Ballentine, Chris J.; Chavrit, Déborah; Dallai, Luigi; Burgess, Ray

2016-03-01

Recycling of marine volatiles back into the mantle at subduction zones has a profound, yet poorly constrained impact on the geochemical evolution of the Earth's mantle. Here we present a combined noble gas and halogen study on mantle xenoliths from the Western Antarctic Rift System (WARS) to better understand the flux of subducted volatiles to the sub continental lithospheric mantle (SCLM) and assess the impact this has on mantle chemistry. The xenoliths are extremely enriched in the heavy halogens (Br and I), with I concentrations up to 1 ppm and maximum measured I/Cl ratios (85.2 × 10-3) being ∼2000 times greater than mid ocean ridge basalts (MORB). The Br/Cl and I/Cl ratios of the xenoliths span a range from MORB-like ratios to values similar to marine pore fluids and serpentinites, whilst the 84Kr/36Ar and 130Xe/36Ar ratios range from modern atmosphere to oceanic sediments. This indicates that marine derived volatiles have been incorporated into the SCLM during an episode of subduction related metasomatism. Helium isotopic analysis of the xenoliths show average 3He/4He ratios of 7.5 ± 0.5 RA (where RA is the 3He/4He ratio of air = 1.39 × 10-6), similar to that of MORB. The 3He/4He ratios within the xenoliths are higher than expected for the xenoliths originating from the SCLM which has been extensively modified by the addition of subducted volatiles, indicating that the SCLM beneath the WARS must have seen a secondary alteration from the infiltration and rise of asthenospheric fluids/melts as a consequence of rifting and lithospheric thinning. Noble gases and halogens within these xenoliths have recorded past episodes of volatile interaction within the SCLM and can be used to reconstruct a tectonic history of the WARS. Marine halogen and noble gas signatures within the SCLM xenoliths provide evidence for the introduction and retention of recycled volatiles within the SCLM by subduction related metasomatism, signifying that not all volatiles that survive subduction are mixed efficiently through the convecting mantle. The global SCLM therefore represents a potentially important reservoir for the long term residence of subducted volatiles.

Ordered distribution of I and Cl in the low-temperature crystal structure of mutnovskite, Pb{sub 4}As{sub 2}S{sub 6}ICl: An X-ray single-crystal study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bindi, Luca; Garavelli, Anna; Pinto, Daniela

2008-02-15

To study the temperature-dependent structural changes and to analyze the crystal chemical behavior of the halogens as a function of temperature, a crystal of the recently discovered mineral mutnovskite, ideally Pb{sub 2}AsS{sub 3}(I,Cl,Br), has been investigated by X-ray single-crystal diffraction methods at 300 and 110 K. At room temperature (RT) mutnovskite was confirmed to possess a centrosymmetric structure-type, space group Pnma, while at low temperature (110 K) it adopts a non-centrosymmetric orthorhombic structure-type, space group Pnm2{sub 1}, with a=11.5394(9) A, b=6.6732(5) A, c=9.3454(7) A, V=719.64(9) A{sup 3} and Z=2. Mutnovskite reconverts to the centrosymmetric-type upon returning to RT thus indicatingmore » that the phase transition is completely reversible in character. The refinement of the LT-structure leads to a residual factor R=0.0336 for 1827 independent observed reflections [F{sub o}>4{sigma}(F{sub o})] and 80 variables. The crystal structure of cooled mutnovskite is topologically identical to that observed at RT and the slight structural changes occurring during the phase transition Pnma{yields}Pnm2{sub 1} are mainly restricted to the coordination polyhedra around Pb. The structure solution revealed that I and Cl are ordered into two specific sites. Indeed, the unique mixed (I,Cl) position in the RT-structure (Wyckoff position 4c) transforms into two 2a Wyckoff positions in the LT-structure hosting I and Cl, respectively. - Graphical abstract: In the crystal structure of mutnovskite at 110 K the two halogens I and Cl are ordered into two specific sites and only slight changes in the coordination environment around Pb atoms occur during the phase transition Pnma{yields}Pnm2{sub 1} from the RT-structure to the LT-structure. Two kinds of layers alternating along a are present in the LT-structure: Layer I contains Cl atoms and [001] columns of Pb1 and Pb4 prisms, layer II contains I atoms and [001] columns of Pb2 and Pb3 prisms.« less

Investigating Planetary Volatile Accretion Mechanisms Using the Halogens

NASA Astrophysics Data System (ADS)

Ballentine, C. J.; Clay, P. L.; Burgess, R.; Busemann, H.; Ruzié, L.; Joachim, B.; Day, J. M.

2014-12-01

Depletion of the volatile elements in the Earth relative to the CI chondrites is roughly correlated with volatility, or decreasing condensation temperature. For the heavy halogen group elements (Cl, Br and I), volatility alone does not account for their apparent depletion, which early data has suggested is far greater than predicted [1-2]. Such depletion has been used to argue for the preferential loss of halogens by, amongst other processes, impact-driven erosive loss from Earth's surface [2]. Little consensus exists as to why the halogens should exhibit such preferential behavior during accretionary processes. Early efforts to constrain halogen abundance and understand their behavior in both Earth and planetary materials [3-6] have been hampered by their typically low abundance (ppb level) in most geologic materials. We present the results of halogen analysis of 23 chondrite samples, selected to represent diverse groups and petrologic type. Halogen abundances were measured by neutron irradiation noble gas mass spectrometry (NI-NGMS). Significant concentration heterogeneity is observed within some samples. However, a single Br/Cl and I/Cl ratio of 1.9 ± 0.2 (x 10-3) and 335 ± 10 (x 10-6) can be defined for carbonaceous chondrites with a good correlation between Br and Cl (R2 = 0.97) and between I and Cl (R2 = 0.84). Ratios of I/Cl overlap with terrestrial estimates of Bulk Silicate Earth and Mid Ocean Ridge Basalts. Similarly, good correlations are derived for enstatite (E) chondrites and a sulfide- and halogen- rich subset of E-chondrites. Chlorine abundances of CI (Orgueil) in this study are lower by factor of ~ 3 than the value of ~ 700 ppm Cl (compilation in [1]). Our results are similar to early discarded low values for Ivuna and Orgueil from [5,6] and agree more closely with values for CM chondrites. Halogens may not be as depleted in Earth as previously suggested, or a high degree of heterogeneity in the abundance of these volatile elements in carbonaceous chondrites should be considered when we assess Earth's halogen abundance relative to CI. [1] Lodders (2003) Astr J 591:1220-47. [2] Sharp et al. (2013) EPSL 369/70: 71-7. [3] Dreibus et al. (1979) Phys Chem Earth 11:33-8. [4] Goles et al. (1967) GCA 31: 1771-7. [5] Reed and Allen (1966) GCA 30: 779-800. [6] Greenland & Lovering (1965) GCA 29: 821-58.

Hydration of the Atlantis Massif: Halogen, Noble Gas and In-Situ δ18O Constraints

NASA Astrophysics Data System (ADS)

Williams, M. J.; Kendrick, M. A.; Rubatto, D.

2017-12-01

A combination of halogen (Cl, Br, I), noble gases (He, Ne, Ar, Kr and Xe) and in situ oxygen isotope analysis have been utilized to investigate the fluid-mobile element record of hydration and alteration processes at the Atlantis Massif (30°N on the Mid-Atlantic Ridge). The sample suite investigated includes serpentinite, talc-amphibole ± chlorite schist and hydrated gabbro recovered by seafloor drilling undertaken at sites on a transect across the Atlantis Massif during IODP Expedition 357. Serpentine mesh and veins analysed in-situ by SHRIMP SI exhibit δ18O from 6‰ down to ≈0‰, suggesting serpentinization temperatures of 150 to >280°C and water/rock ratios >5. Differences of 1.5-2.5‰ are observed between adjacent generations of serpentine, but the δ18O range is similar at each investigated drilling site. Halogen and noble gas abundances in serpentinites, talc-amphibole schist and hydrated gabbro have been measured by noble gas mass spectrometry of both irradiated and non-irradiated samples. Serpentinites contain low abundances of halogens and noble gases (e.g. 70-430 ppm Cl, 4.7-12.2 x 10-14 mol/g 36Ar) relative to other seafloor serpentinites. The samples have systematically different Br/Cl and I/Cl ratios related to their mineralogy. Serpentinites retain mantle-like Br/Cl with a wide variation in I/Cl that stretches toward seawater values. Talc-amphibole schists exhibit depletion of Br and I relative to Cl with increasing Cl abundances, suggesting tremolite exerts strong control on halogen abundance ratios. Serpentinites show no evidence of interaction with halogen-rich sedimentary pore fluids. Iodine abundances are variable across serpentinites, and are decoupled from Br and Cl; iodine enrichment (up to 530 ppb) is observed within relatively oxidised and clay-bearing samples. Serpentinized harzburgites exhibit distinct depletion of Kr and Xe relative to atmospheric 36Ar in seawater. Oxygen isotope compositions and low abundances of both halogens and noble gases are consistent with high water/rock ratios. Successive generations of serpentine have δ18O trends suggesting exposure to higher W/R ratios during exhumation and deformation of the massif. Low noble gas abundances of may also be influenced by thermal loss related to impregnation and intrusion of the Massif by gabbros and dolerites.

Recent advances of mid-infrared compact, field deployable sensors: principles and applications

NASA Astrophysics Data System (ADS)

Tittel, Frank; Gluszek, Aleksander; Hudzikowski, Arkadiusz; Dong, Lei; Li, Chunguang; Patimisco, Pietro; Sampaolo, Angelo; Spagnolo, Vincenzo; Wojtas, Jacek

2016-04-01

The recent development of compact interband cascade lasers(ICLs) and quantum cascade lasers (QCLs) based trace gas sensors will permit the targeting of strong fundamental rotational-vibrational transitions in the mid-infrared which are one to two orders of magnitude more intense than transitions in the overtone and combination bands in the near-infrared. This has led to the design and fabrication of mid-infrared compact, field deployable sensors for use in the petrochemical industry, environmental monitoring and atmospheric chemistry. Specifically, the spectroscopic detection and monitoring of four molecular species, methane (CH4) [1], ethane (C2H6), formaldehyde (H2CO) [2] and hydrogen sulphide (H2S) [3] will be described. CH4, C2H6 and H2CO can be detected using two detection techniques: mid-infrared tunable laser absorption spectroscopy (TDLAS) using a compact multi-pass gas cell and quartz enhanced photoacoustic spectroscopy (QEPAS). Both techniques utilize state-of-the-art mid-IR, continuous wave (CW), distributed feedback (DFB) ICLs and QCLs. TDLAS was performed with an ultra-compact 54.6m effective optical path length innovative spherical multipass gas cell capable of 435 passes between two concave mirrors separated by 12.5 cm. QEPAS used a small robust absorption detection module (ADM) which consists of a quartz tuning fork (QTF), two optical windows, gas inlet/outlet ports and a low noise frequency pre-amplifier. Wavelength modulation and second harmonic detection were employed for spectral data processing. TDLAS and QEPAS can achieve minimum detectable absorption losses in the range from 10-8 to 10-11cm-1/Hz1/2. Several recent examples of real world applications of field deployable gas sensors will be described. For example, an ICL based TDLAS sensor system is capable of detecting CH4 and C2H6 concentration levels of 1 ppb in a 1 sec. sampling time, using an ultra-compact, robust sensor architecture. H2S detection was realized with a THz QEPAS sensor system using a custom quartz tuning fork (QTF) with a new geometry and a QCL emitting at 2.913 THz [4]. Furthermore, two new approaches aimed to achieve enhanced detection sensitivities with QEPAS based sensing can be realized. The first method will make use of a compact optical power buildup cavity, which achieves significantly lower minimum detectable trace gas concentration levels of < 10 pptv. The second approach will use custom fabricated QTFs capable of improved detection sensitivity. Acknowledgements F.K. Tittel acknowledges support by the National Science Foundation (NSF) ERC MIRTHE award, the Robert Welch Foundation (Grant C-0586) and DOE ARPA-E Monitor Proram. L. Dong acknowledges support by NSF-China (Grant #s. 61275213, 61108030), J. Wojtas acknowledges support by The National Centre for Research and Development, Poland (project ID: 179616). References [1] L. Dong, C. Li, N. P. Sanchez, A. K. Gluszek, R. Griffin and F. K. Tittel;" Compact CH4 sensor system based on a continuous-wave, low power consumption, room temperature interband cascade laser", Appl. Phys Lett. 108, 011106 (2016). [2] L. Dong, Y. Yu, C. Li, S. So, and F.K. Tittel, "Ppb-level formaldehyde detection using a CW room-temperature interband cascade laser and a miniature dense pattern multipass cell" Optics Express; 23, 19821-19830 (2015). [3] V. Spagnolo, P. Patimisco, R. Pennetta, A. Sampaolo, G. Scamarcio, M. Vitiello, and F.K. Tittel, "THz Quartz-enhanced photoacoustic sensor for H2S trace gas detection", Opt. Exp. 23, 7574-7582 (2015). [4] A. Sampaolo, P. Patimisco, L. Dong , A. Geras, S, G. Scamarcio' T. Starecki, F.K Tittel, V. Spagnolo; "Quartz-Enhanced Photoacoustic Spectroscopy exploiting tuning fork overtone modes", Appl. Phys Lett. 107, 231102 (2015).

Detection of Atmospheric Methyl Mercaptan Using Wavelength Modulation Spectroscopy with Multicomponent Spectral Fitting

PubMed Central

Du, Zhenhui; Wan, Jiaxin; Li, Jinyi; Luo, Gang; Gao, Hong; Ma, Yiwen

2017-01-01

Detection of methyl mercaptan (CH3SH) is essential for environmental atmosphere assessment and exhaled-breath analysis. This paper presents a sensitive CH3SH sensor based on wavelength modulation spectroscopy (WMS) with a mid-infrared distributed feedback interband cascade laser (DFB-ICL). Multicomponent spectral fitting was used not only to enhance the sensitivity of the sensor but also to determine the concentration of interferents (atmospheric water and methane). The results showed that the uncertainties in the measurement of CH3SH, H2O, and CH4 were less than 1.2%, 1.7% and 2.0%, respectively, with an integration time of 10 s. The CH3SH detection limit was as low as 7.1 ppb with an integration time of 295 s. Overall, the reported sensor, boasting the merits of high sensitivity, can be used for atmospheric methyl mercaptan detection, as well as multiple components detection of methyl mercaptan, water, and methane, simultaneously. PMID:28212311

The IceCube data acquisition system: Signal capture, digitization, and timestamping

NASA Astrophysics Data System (ADS)

Abbasi, R.; Ackermann, M.; Adams, J.; Ahlers, M.; Ahrens, J.; Andeen, K.; Auffenberg, J.; Bai, X.; Baker, M.; Barwick, S. W.; Bay, R.; Bazo Alba, J. L.; Beattie, K.; Becka, T.; Becker, J. K.; Becker, K.-H.; Berghaus, P.; Berley, D.; Bernardini, E.; Bertrand, D.; Besson, D. Z.; Bingham, B.; Blaufuss, E.; Boersma, D. J.; Bohm, C.; Bolmont, J.; Böser, S.; Botner, O.; Braun, J.; Breeder, D.; Burgess, T.; Carithers, W.; Castermans, T.; Chen, H.; Chirkin, D.; Christy, B.; Clem, J.; Cowen, D. F.; D'Agostino, M. V.; Danninger, M.; Davour, A.; Day, C. T.; Depaepe, O.; De Clercq, C.; Demirörs, L.; Descamps, F.; Desiati, P.; de Vries-Uiterweerd, G.; DeYoung, T.; Diaz-Velez, J. C.; Dreyer, J.; Dumm, J. P.; Duvoort, M. R.; Edwards, W. R.; Ehrlich, R.; Eisch, J.; Ellsworth, R. W.; Engdegård, O.; Euler, S.; Evenson, P. A.; Fadiran, O.; Fazely, A. R.; Feusels, T.; Filimonov, K.; Finley, C.; Foerster, M. M.; Fox, B. D.; Franckowiak, A.; Franke, R.; Gaisser, T. K.; Gallagher, J.; Ganugapati, R.; Gerhardt, L.; Gladstone, L.; Glowacki, D.; Goldschmidt, A.; Goodman, J. A.; Gozzini, R.; Grant, D.; Griesel, T.; Groß, A.; Grullon, S.; Gunasingha, R. M.; Gurtner, M.; Ha, C.; Hallgren, A.; Halzen, F.; Han, K.; Hanson, K.; Hardtke, R.; Hasegawa, Y.; Haugen, J.; Hays, D.; Heise, J.; Helbing, K.; Hellwig, M.; Herquet, P.; Hickford, S.; Hill, G. C.; Hodges, J.; Hoffman, K. D.; Hoshina, K.; Hubert, D.; Huelsnitz, W.; Hughey, B.; Hülß, J.-P.; Hulth, P. O.; Hultqvist, K.; Hussain, S.; Imlay, R. L.; Inaba, M.; Ishihara, A.; Jacobsen, J.; Japaridze, G. S.; Johansson, H.; Jones, A.; Joseph, J. M.; Kampert, K.-H.; Kappes, A.; Karg, T.; Karle, A.; Kawai, H.; Kelley, J. L.; Kiryluk, J.; Kislat, F.; Klein, S. R.; Kleinfelder, S.; Klepser, S.; Kohnen, G.; Kolanoski, H.; Köpke, L.; Kowalski, M.; Kowarik, T.; Krasberg, M.; Kuehn, K.; Kujawski, E.; Kuwabara, T.; Labare, M.; Laihem, K.; Landsman, H.; Lauer, R.; Laundrie, A.; Leich, H.; Leier, D.; Lewis, C.; Lucke, A.; Ludvig, J.; Lundberg, J.; Lünemann, J.; Madsen, J.; Maruyama, R.; Mase, K.; Matis, H. S.; McParland, C. P.; Meagher, K.; Meli, A.; Merck, M.; Messarius, T.; Mészáros, P.; Minor, R. H.; Miyamoto, H.; Mohr, A.; Mokhtarani, A.; Montaruli, T.; Morse, R.; Movit, S. M.; Münich, K.; Muratas, A.; Nahnhauer, R.; Nam, J. W.; Nießen, P.; Nygren, D. R.; Odrowski, S.; Olivas, A.; Olivo, M.; Ono, M.; Panknin, S.; Patton, S.; Pérez de los Heros, C.; Petrovic, J.; Piegsa, A.; Pieloth, D.; Pohl, A. C.; Porrata, R.; Potthoff, N.; Pretz, J.; Price, P. B.; Przybylski, G. T.; Rawlins, K.; Razzaque, S.; Redl, P.; Resconi, E.; Rhode, W.; Ribordy, M.; Rizzo, A.; Robbins, W. J.; Rodrigues, J. P.; Roth, P.; Rothmaier, F.; Rott, C.; Roucelle, C.; Rutledge, D.; Ryckbosch, D.; Sander, H.-G.; Sarkar, S.; Satalecka, K.; Sandstrom, P.; Schlenstedt, S.; Schmidt, T.; Schneider, D.; Schulz, O.; Seckel, D.; Semburg, B.; Seo, S. H.; Sestayo, Y.; Seunarine, S.; Silvestri, A.; Smith, A. J.; Song, C.; Sopher, J. E.; Spiczak, G. M.; Spiering, C.; Stanev, T.; Stezelberger, T.; Stokstad, R. G.; Stoufer, M. C.; Stoyanov, S.; Strahler, E. A.; Straszheim, T.; Sulanke, K.-H.; Sullivan, G. W.; Swillens, Q.; Taboada, I.; Tarasova, O.; Tepe, A.; Ter-Antonyan, S.; Tilav, S.; Tluczykont, M.; Toale, P. A.; Tosi, D.; Turčan, D.; van Eijndhoven, N.; Vandenbroucke, J.; Van Overloop, A.; Viscomi, V.; Vogt, C.; Voigt, B.; Vu, C. Q.; Wahl, D.; Walck, C.; Waldenmaier, T.; Waldmann, H.; Walter, M.; Wendt, C.; Westerhof, S.; Whitehorn, N.; Wharton, D.; Wiebusch, C. H.; Wiedemann, C.; Wikström, G.; Williams, D. R.; Wischnewski, R.; Wissing, H.; Woschnagg, K.; Xu, X. W.; Yodh, G.; Yoshida, S.; IceCube Collaboration

2009-04-01

IceCube is a km-scale neutrino observatory under construction at the South Pole with sensors both in the deep ice (InIce) and on the surface (IceTop). The sensors, called Digital Optical Modules (DOMs), detect, digitize and timestamp the signals from optical Cherenkov-radiation photons. The DOM Main Board (MB) data acquisition subsystem is connected to the central DAQ in the IceCube Laboratory (ICL) by a single twisted copper wire-pair and transmits packetized data on demand. Time calibration is maintained throughout the array by regular transmission to the DOMs of precisely timed analog signals, synchronized to a central GPS-disciplined clock. The design goals and consequent features, functional capabilities, and initial performance of the DOM MB, and the operation of a combined array of DOMs as a system, are described here. Experience with the first InIce strings and the IceTop stations indicates that the system design and performance goals have been achieved.

Exploration of freely available web-interfaces for comparative homology modelling of microbial proteins

PubMed Central

Nema, Vijay; Pal, Sudhir Kumar

2013-01-01

Aim: This study was conducted to find the best suited freely available software for modelling of proteins by taking a few sample proteins. The proteins used were small to big in size with available crystal structures for the purpose of benchmarking. Key players like Phyre2, Swiss-Model, CPHmodels-3.0, Homer, (PS)2, (PS)2-V2, Modweb were used for the comparison and model generation. Results: Benchmarking process was done for four proteins, Icl, InhA, and KatG of Mycobacterium tuberculosis and RpoB of Thermus Thermophilus to get the most suited software. Parameters compared during analysis gave relatively better values for Phyre2 and Swiss-Model. Conclusion: This comparative study gave the information that Phyre2 and Swiss-Model make good models of small and large proteins as compared to other screened software. Other software was also good but is often not very efficient in providing full-length and properly folded structure. PMID:24023424

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

PubMed Central

Roos, Wynand Paul; Krumm, Andrea

2016-01-01

Histone/protein deacetylases play multiple roles in regulating gene expression and protein activation and stability. Their deregulation during cancer initiation and progression cause resistance to therapy. Here, we review the role of histone deacetylases (HDACs) and the NAD+ dependent sirtuins (SIRTs) in the DNA damage response (DDR). These lysine deacetylases contribute to DNA repair by base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), non-homologous end joining (NHEJ), homologous recombination (HR) and interstrand crosslink (ICL) repair. Furthermore, we discuss possible mechanisms whereby these histone/protein deacetylases facilitate the switch between DNA double-strand break (DSB) repair pathways, how SIRTs play a central role in the crosstalk between DNA repair and cell death pathways due to their dependence on NAD+, and the influence of small molecule HDAC inhibitors (HDACi) on cancer cell resistance to genotoxin based therapies. Throughout the review, we endeavor to identify the specific HDAC targeted by HDACi leading to therapy sensitization. PMID:27738139

Ppb-level formaldehyde detection using a CW room-temperature interband cascade laser and a miniature dense pattern multipass gas cell

DOE PAGES

Dong, Lei; Yu, Yajun; Li, Chunguang; ...

2015-07-27

A ppb-level formaldehyde (H 2CO) sensor was developed using a thermoelectrically cooled (TEC), continuous-wave (CW) room temperature interband cascade laser (ICL) emitting at 3.59 μm and a miniature dense pattern multipass gas cell with >50 m optical path length. Performance of the sensor was investigated with two measurement schemes: direct absorption (DAS) and wavelength modulation spectroscopy (WMS). With an integration time of less than 1.5 second, a detection limit of ~3 ppbv for H 2CO measurement with precision of 1.25 ppbv for DAS and 0.58 ppbv for WMS, respectively, was achieved without zero air based background subtraction. An Allan-Werle variancemore » analysis indicated that the precisions can be further improved to 0.26 ppbv @ 300s for DAS and 69 pptv @ 90 s for WMS, respectively. Finally, a side-by-side comparison between two measurement schemes is also discussed in detail.« less

Visualization of Radiation Environment on Mars: Assessment with MARIE Measurements

NASA Technical Reports Server (NTRS)

Saganti, P.; Cucinotta, F.; Zeitlin, C.; Cleghorn, T.; Flanders, J.; Riman, F.; Hu, X.; Pinsky, L.; Lee, K.; Anderson, V.;

Department of the Air Force FY 1995 Budget Estimates Submitted to Congress February 1994. Military Personnel, Air National Guard

DTIC Science & Technology

1994-02-01

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Development and field application of a 6-bottle serial gas-tight fluid sampler for collecting seafloor cold seep and hydrothermal vent fluids with autonomous operation capability

NASA Astrophysics Data System (ADS)

Wu, S.; Ding, K.; Yang, C.; Seyfried, W. E., Jr.; Tan, C.; Schaen, A. T.; Luhmann, A. J.

2014-12-01

A 6-bottle serial gas-tight sampler (so-called "six-shooter") was developed for application with deep-sea vent fluids. The new device is composed of a custom-made 6-channel valve manifold and six sampling bottles which are circularly distributed around the valve manifold. Each valve channel consists of a high-pressure titanium cartridge valve and a motor-driven actuator. A sampling snorkel is connected to the inlet of the manifold that delivers the incoming fluid to different bottles. Each sampling bottle has a 160 ml-volume chamber and an accumulator chamber inside where compressed nitrogen is used to maintain the sample at near in-situ pressure. An electronics chamber that is located at the center of the sampler is used to carry out all sampling operations, autonomously, if desired. The sampler is of a compact circular configuration with a diameter of 26 cm and a length of 54 cm. During the SVC cruise AT 26-12, the sampler was deployed by DSV2 Alvin at a cold seep site MC036 with a depth of 1090 m in the Gulf of Mexico. The sampler collected fluid samples automatically following the tidal cycle to monitor the potential impact of the tide cycle on the fluid chemistry of cold seep in a period of two day. During the cruise AT 26-17, the sampler was used with newly upgraded DSV2 Alvin three times at the hydrothermal vent sites along Axial Seamount and Main Endeavor Field on Juan de Fuca Ridge. During a 4-day deployment at Anemone diffuse site (Axial Caldera), the sampler was set to work in an autonomous mode to collect fluid samples according to the preset interval. During other dives, the sampler was manually controlled via ICL (Inductively Coupled Link) communication through the hull. Gas-tight fluid samples were collected from different hydrothermal vents with temperatures between 267 ℃ and 335 ℃ at the depth up to 2200 m. The field results indicate unique advantages of the design. It can be deployed in extended time period with remote operation or working autonomously taking gas-tight fluid samples. If used with HOV or ROV, it will reduce basket space occupation and ICL communication cables compared to traditional single-bottle gas-tight samplers. This time serial gas-tight fluid sampler will be further developed into a 36 bottle system for remote operation with seafloor cabled observatory.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Jun; Byrne, Noel; Wang, John

Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40–MK-8666 binary complex reveals an induced-fit conformational couplingmore » between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.« less

Prime Contract Awards Alphabetically by Contractor, by State or Country, and Place. Part 1 (101 International-Allied Signal Inc)

DTIC Science & Technology

1990-01-01

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Channel-resolved photo- and Auger-electron spectroscopy of halogenated hydrocarbons

NASA Astrophysics Data System (ADS)

Ablikim, Utuq; Kaderiya, B.; Kumarapan, V.; Kushawaha, R.; Rudenko, A.; Rolles, D.; Xiong, H.; Berrah, N.; Bomme, C.; Savelyev, E.; Kilcoyne, D.

2016-05-01

Inner-shell photoelectron and Auger electron spectra of polyatomic molecules such as halogenated hydrocarbons are typically hard to interpret and assign due to many overlapping states that form broad bands even in high-resolution measurements. With the help of electron-ion-ion coincidence measurements performed using the velocity map imaging technique, we are able to detect high-energy (<= 150 eV) photo- and Auger electrons in coincidence with two- or many-body ionic fragmentation channels. Such channel-resolved measurements allow disentangling the overlapping electronic structures and help assigning individual components of the electron spectra to specific potential surfaces and final states. In this work, we present measurements on CH3 I, CH2 IBr, and CH2 ICl molecules in the gas-phase using soft x-ray light provided by the Advanced Light Source at LBNL. This project is supported by the DOE, Office of Science, BES, Division of Chemical, Geological and Biological Sciences under Award Number DE-FG02-86ER13491 (U.A., B.K., V.K., A.R., D.R.) and Award Number DE-SC0012376 (H.X., N.B.).

Fanconi Anemia: A DNA repair disorder characterized by accelerated decline of the hematopoietic stem cell compartment and other features of aging.

PubMed

Brosh, Robert M; Bellani, Marina; Liu, Yie; Seidman, Michael M

2017-01-01

Fanconi Anemia (FA) is a rare autosomal genetic disorder characterized by progressive bone marrow failure (BMF), endocrine dysfunction, cancer, and other clinical features commonly associated with normal aging. The anemia stems directly from an accelerated decline of the hematopoietic stem cell compartment. Although FA is a complex heterogeneous disease linked to mutations in 19 currently identified genes, there has been much progress in understanding the molecular pathology involved. FA is broadly considered a DNA repair disorder and the FA gene products, together with other DNA repair factors, have been implicated in interstrand cross-link (ICL) repair. However, in addition to the defective DNA damage response, altered epigenetic regulation, and telomere defects, FA is also marked by elevated levels of inflammatory mediators in circulation, a hallmark of faster decline in not only other hereditary aging disorders but also normal aging. In this review, we offer a perspective of FA as a monogenic accelerated aging disorder, citing the latest evidence for its multi-factorial deficiencies underlying its unique clinical and cellular features. Published by Elsevier B.V.

Xenopus egg extract: A powerful tool to study genome maintenance mechanisms.

PubMed

Hoogenboom, Wouter S; Klein Douwel, Daisy; Knipscheer, Puck

2017-08-15

DNA repair pathways are crucial to maintain the integrity of our genome and prevent genetic diseases such as cancer. There are many different types of DNA damage and specific DNA repair mechanisms have evolved to deal with these lesions. In addition to these repair pathways there is an extensive signaling network that regulates processes important for repair, such as cell cycle control and transcription. Despite extensive research, DNA damage repair and signaling are not fully understood. In vitro systems such as the Xenopus egg extract system, have played, and still play, an important role in deciphering the molecular details of these processes. Xenopus laevis egg extracts contain all factors required to efficiently perform DNA repair outside a cell, using mechanisms conserved in humans. These extracts have been used to study several genome maintenance pathways, including mismatch repair, non-homologous end joining, ICL repair, DNA damage checkpoint activation, and replication fork stability. Here we describe how the Xenopus egg extract system, in combination with specifically designed DNA templates, contributed to our detailed understanding of these pathways. Copyright © 2017. Published by Elsevier Inc.

Photo-acoustic sensor for detection of oil contamination in compressed air systems.

PubMed

Lassen, Mikael; Harder, David Baslev; Brusch, Anders; Nielsen, Ole Stender; Heikens, Dita; Persijn, Stefan; Petersen, Jan C

2017-02-06

We demonstrate an online (in-situ) sensor for continuous detection of oil contamination in compressed air systems complying with the ISO-8573 standard. The sensor is based on the photo-acoustic (PA) effect. The online and real-time PA sensor system has the potential to benefit a wide range of users that require high purity compressed air. Among these are hospitals, pharmaceutical industries, electronics manufacturers, and clean room facilities. The sensor was tested for sensitivity, repeatability, robustness to molecular cross-interference, and stability of calibration. Explicit measurements of hexane (C₆H₁₄) and decane (C₁₀H₂₂) vapors via excitation of molecular C-H vibrations at approx. 2950 cm^-1 (3.38 μm) were conducted with a custom made interband cascade laser (ICL). For the decane measurements a (1 σ) standard deviation (STD) of 0.3 ppb was demonstrated, which corresponds to a normalized noise equivalent absorption (NNEA) coefficient for the prototype PA sensor of 2.8×10^-9 W cm^-1 Hz^1/2.

Apparatus and methods for regeneration of precipitating solvent

DOEpatents

Liu, Guohai; Vimalchand, Pannalal; Peng, Wan Wang; Bonsu, Alexander

2015-08-25

A regenerator that can handle rich loaded chemical solvent containing precipitated absorption reaction products is disclosed. The invention is particularly suitable for separating CO.sub.2 from large gas streams that are typical of power plant processes. The internally circulating liquid stream in the regenerator (ICLS regenerator) rapidly heats-up the in-coming rich solvent stream in a downcomer standpipe as well as decreases the overall concentration of CO.sub.2 in the mixed stream. Both these actions lead to dissolution of precipitates. Any remaining precipitate further dissolves as heat is transferred to the mixed solution with an inverted bayonet tube heat exchanger in the riser portion of the regenerator. The evolving CO.sub.2 bubbles in the riser portion of the regenerator lead to substantial gas hold-up and the large density difference between the solutions in the downcomer standpipe and riser portions promotes internal circulation of the liquid stream in the regenerator. As minor amounts of solvent components present in the exit gas stream are condensed and returned back to the regenerator, pure CO.sub.2 gas stream exits the disclosed regenerator and condenser system.

All Prime Contract Awards by State or Country, Place, and Contractor, Fiscal Year 1985. Part 9 (Aberdeen, Maryland - Woodbine, Maryland).

DTIC Science & Technology

1985-01-01

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NASA 60 GHz intersatellite communication link definition study. Addendum A: Mixed baseband and IF signals

NASA Technical Reports Server (NTRS)

1986-01-01

As part of a definition study for a 60 GHz intersatellite communications link system (ICLS), baseline design concepts for a channelized crosslink were identified. The crosslink would allow communications between geostationary satellites of the planned Tracking and Data Acquisition System (TDAS) and would accommodate a mixture of frequency translation coherent links (bent pipe links) and baseband-in/baseband-out links (mod/demod links). A 60 GHz communication system was developed for sizing and analyzing the crosslink. For the coherent links this system translates incoming signals directly up to the 60 GHz band; trunks the signals across from one satellite to a second satellite at 60 GHz then down converts to the proper frequency for re-transmission from the second satellite without converting to any intermediate frequencies. For the baseband-in/baseband-out links the baseband data is modulated on to the 60 GHz carrier at the transmitting satellite and demodulated at the receiving satellite. The frequency plan, equipment diagrams, and link calculations are presented along with results from sizing and reliability analyses.

Passively mode-locked interband cascade optical frequency combs.

PubMed

Bagheri, Mahmood; Frez, Clifford; Sterczewski, Lukasz A; Gruidin, Ivan; Fradet, Mathieu; Vurgaftman, Igor; Canedy, Chadwick L; Bewley, William W; Merritt, Charles D; Kim, Chul Soo; Kim, Mijin; Meyer, Jerry R

2018-02-20

Since their inception, optical frequency combs have transformed a broad range of technical and scientific disciplines, spanning time keeping to navigation. Recently, dual comb spectroscopy has emerged as an attractive alternative to traditional Fourier transform spectroscopy, since it offers higher measurement sensitivity in a fraction of the time. Midwave infrared (mid-IR) frequency combs are especially promising as an effective means for probing the strong fundamental absorption lines of numerous chemical and biological agents. Mid-IR combs have been realized via frequency down-conversion of a near-IR comb, by optical pumping of a micro-resonator, and beyond 7 μm by four-wave mixing in a quantum cascade laser. In this work, we demonstrate an electrically-driven frequency comb source that spans more than 1 THz of bandwidth centered near 3.6 μm. This is achieved by passively mode-locking an interband cascade laser (ICL) with gain and saturable absorber sections monolithically integrated on the same chip. The new source will significantly enhance the capabilities of mid-IR multi-heterodyne frequency comb spectroscopy systems.

Comparison of two novel in-syringe dispersive liquid-liquid microextraction techniques for the determination of iodide in water samples using spectrophotometry.

PubMed

Kaykhaii, Massoud; Sargazi, Mona

2014-01-01

Two new, rapid methodologies have been developed and applied successfully for the determination of trace levels of iodide in real water samples. Both techniques are based on a combination of in-syringe dispersive liquid-liquid microextraction (IS-DLLME) and micro-volume UV-Vis spectrophotometry. In the first technique, iodide is oxidized with nitrous acid to the colorless anion of ICl2(-) at high concentration of hydrochloric acid. Rhodamine B is added and by means of one step IS-DLLME, the ion-pair formed was extracted into toluene and measured spectrophotometrically. Acetone is used as dispersive solvent. The second method is based on the IS-DLLME microextraction of iodide as iodide/1, 10-phenanthroline-iron((II)) chelate cation ion-pair (colored) into nitrobenzene. Methanol was selected as dispersive solvent. Optimal conditions for iodide extraction were determined for both approaches. Methods are compared in terms of analytical parameters such as precision, accuracy, speed and limit of detection. Both methods were successfully applied to determining iodide in tap and river water samples. Copyright © 2013 Elsevier B.V. All rights reserved.

Interband cascade laser-based ppbv-level mid-infrared methane detection using two digital lock-in amplifier schemes

NASA Astrophysics Data System (ADS)

Song, Fang; Zheng, Chuantao; Yu, Di; Zhou, Yanwen; Yan, Wanhong; Ye, Weilin; Zhang, Yu; Wang, Yiding; Tittel, Frank K.

2018-03-01

A parts-per-billion in volume (ppbv) level mid-infrared methane (CH4) sensor system was demonstrated using second-harmonic wavelength modulation spectroscopy (2 f-WMS). A 3291 nm interband cascade laser (ICL) and a multi-pass gas cell (MPGC) with a 16 m optical path length were adopted in the reported sensor system. Two digital lock-in amplifier (DLIA) schemes, a digital signal processor (DSP)-based DLIA and a LabVIEW-based DLIA, were used for harmonic signal extraction. A limit of detection (LoD) of 13.07 ppbv with an averaging time of 2 s was achieved using the DSP-based DLIA and a LoD of 5.84 ppbv was obtained using the LabVIEW-based DLIA with the same averaging time. A rise time of 0→2 parts-per-million in volume (ppmv) and fall time of 2→0 ppmv were observed. Outdoor atmospheric CH4 concentration measurements were carried out to evaluate the sensor performance using the two DLIA schemes.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruffey, S. H.; Spencer, B. B.; Strachan, D. M.

Four radionuclides have been identified as being sufficiently volatile in the reprocessing of nuclear fuel that their gaseous release needs to be controlled to meet regulatory requirements (Jubin et al. 2011, 2012). These radionuclides are 3H, 14C, 85Kr, and 129I. Of these, 129I has the longest half-life and potentially high biological impact. Accordingly, control of the release of 129I is most critical with respect to the regulations for the release of radioactive material in stack emissions. It is estimated that current EPA regulations (EPA 2010) would require any reprocessing plant in the United States to limit 129I release to lessmore » than 0.05 Ci/MTIHM for a typical fuel burnup of 55 gigawatt days per metric tonne (GWd/t) (Jubin 2011). The study of inorganic iodide in off-gas systems has been almost exclusively limited to I2 and the focus of organic iodide studies has been CH3I. In this document, we provide the results of an examination of publically available literature that is relevant to the presence and sources of both inorganic and organic iodine-bearing species in reprocessing plants. We especially focus on those that have the potential to be poorly sequestered with traditional capture methodologies. Based on the results of the literature survey and some limited thermodynamic modeling, the inorganic iodine species hypoiodous acid (HOI) and iodine monochloride (ICl) were identified as potentially low-sorbing iodine species that could present in off-gas systems. Organic species of interest included both short chain alkyl iodides such as methyl iodide (CH3I) and longer alkyl iodides up to iodododecane (C10H21I). It was found that fuel dissolution may provide conditions conducive to HOI formation and has been shown to result in volatile long-chain alkyl iodides, though these may not volatilize until later in the reprocessing sequence. Solvent extraction processes were found to be significant sources of various organic iodine-bearing species; formation of these was facilitated by the presence of radiolytic decomposition products resulting from radiolysis of tri-n-butyl phosphate and dodecane. Primarily inorganic iodine compounds were expected from waste management processes, including chlorinated species such as ICl. Critical knowledge gaps that must still be addressed include confirmation of the existence and quantification of low-sorbing species in the off-gas of reprocessing facilities. The contributions from penetrating forms of iodine to the plant DF are largely unknown and highly dependent on the magnitude of their presence. These species are likely to be more difficult to remove and it is likely that their sequestration could be improved through the use of different sorbents, through design modifications of the off-gas capture system, or through chemical conversion prior to iodine abatement that would produce more easily captured forms.« less

Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair.

PubMed

Leung, Justin Wai Chung; Wang, Yucai; Fong, Ka Wing; Huen, Michael Shing Yan; Li, Lei; Chen, Junjie

2012-03-20

The Fanconi anemia (FA) pathway participates in interstrand cross-link (ICL) repair and the maintenance of genomic stability. The FA core complex consists of eight FA proteins and two Fanconi anemia-associated proteins (FAAP24 and FAAP100). The FA core complex has ubiquitin ligase activity responsible for monoubiquitination of the FANCI-FANCD2 (ID) complex, which in turn initiates a cascade of biochemical events that allow processing and removal of cross-linked DNA and thereby promotes cell survival following DNA damage. Here, we report the identification of a unique component of the FA core complex, namely, FAAP20, which contains a RAD18-like ubiquitin-binding zinc-finger domain. Our data suggest that FAAP20 promotes the functional integrity of the FA core complex via its direct interaction with the FA gene product, FANCA. Indeed, somatic knockout cells devoid of FAAP20 displayed the hallmarks of FA cells, including hypersensitivity to DNA cross-linking agents, chromosome aberrations, and reduced FANCD2 monoubiquitination. Taking these data together, our study indicates that FAAP20 is an important player involved in the FA pathway.

Fanconi anemia (FA) binding protein FAAP20 stabilizes FA complementation group A (FANCA) and participates in interstrand cross-link repair

PubMed Central

Leung, Justin Wai Chung; Wang, Yucai; Fong, Ka Wing; Huen, Michael Shing Yan; Li, Lei; Chen, Junjie

2012-01-01

The Fanconi anemia (FA) pathway participates in interstrand cross-link (ICL) repair and the maintenance of genomic stability. The FA core complex consists of eight FA proteins and two Fanconi anemia-associated proteins (FAAP24 and FAAP100). The FA core complex has ubiquitin ligase activity responsible for monoubiquitination of the FANCI-FANCD2 (ID) complex, which in turn initiates a cascade of biochemical events that allow processing and removal of cross-linked DNA and thereby promotes cell survival following DNA damage. Here, we report the identification of a unique component of the FA core complex, namely, FAAP20, which contains a RAD18-like ubiquitin-binding zinc-finger domain. Our data suggest that FAAP20 promotes the functional integrity of the FA core complex via its direct interaction with the FA gene product, FANCA. Indeed, somatic knockout cells devoid of FAAP20 displayed the hallmarks of FA cells, including hypersensitivity to DNA cross-linking agents, chromosome aberrations, and reduced FANCD2 monoubiquitination. Taking these data together, our study indicates that FAAP20 is an important player involved in the FA pathway. PMID:22396592

Hematopoietic recovery after administration of deferasirox for transfusional iron overload in a case of myelodysplastic syndrome.

PubMed

OKABE, Hiroshi; SUZUKI, Takahiro; OMORI, Tsukasa; MORI, Masaki; UEHARA, Eisuke; HATANO, Kaoru; UEDA, Masuzu; MATSUYAMA, Tomohiro; TOSHIMA, Masaki; QZAKI, Katsutoshi; NAGAI, Tadashi; MUROI, Kazuo; OZAWA, Keiya

2009-11-01

Deferasirox (DFX) is a newly developed oral iron chelator that enables effective chelation with once daily administration. We describe here a case of transfusional-iron overloaded patient who experienced hematopoietic recovery after DFX administration. A 75-year-old woman with iron overload, who had been diagnosed with MDS (RCMD) and had received a transfusion of red blood cells and platelets regularly for 3 years, enrolled in the phase I clinical trial of ICL670 (DFX) in Japan. DFX administration steadily decreased her serum ferritin levels and chelated overloaded iron effectively. Interestingly, a year after initiation of the trial, she needed fewer blood transfusions, and no more transfusions after the 17th month of the trial. Even after suspending transfusions, her hemoglobin level and platelet count increased continuously, and she now has stable disease without blood transfusions. She has not received any specific treatment for MDS during this period. Examination of the bone marrow aspirates in the 35th month revealed dysplastic cells, indicating no remarkable change in the state of MDS. This case suggests that excess iron hampers hematopoiesis and that adequate iron chelation may improve hematological data in some iron-overloaded patients.

Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia.

PubMed

Rickman, Kimberly A; Lach, Francis P; Abhyankar, Avinash; Donovan, Frank X; Sanborn, Erica M; Kennedy, Jennifer A; Sougnez, Carrie; Gabriel, Stacey B; Elemento, Olivier; Chandrasekharappa, Settara C; Schindler, Detlev; Auerbach, Arleen D; Smogorzewska, Agata

2015-07-07

Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Comparison of surgical time and IOP spikes with two ophthalmic viscosurgical devices following Visian STAAR (ICL, V4c model) insertion in the immediate postoperative period.

PubMed

Ganesh, Sri; Brar, Sheetal

2016-01-01

To compare the effect of two ocular viscosurgical devices (OVDs) on intraocular pressure (IOP) and surgical time in immediate postoperative period after bilateral implantable collamer lens (using the V4c model) implantation. A total of 20 eligible patients were randomized to receive 2% hydroxypropylmethylcellulose (HPMC) in one eye and 1% hyaluronic acid in fellow eye. Time taken for complete removal of OVD and total surgical time were recorded. At the end of surgery, IOP was adjusted between 15 and 20 mmHg in both the eyes. Mean time for complete OVD evacuation and total surgical time were significantly higher in the HPMC group (P=0.00). Four eyes in the HPMC group had IOP spike, requiring treatment. IOP values with noncontact tonometry at 1, 2, 4, 24, and 48 hours were not statistically significant (P>0.05) for both the groups. The study concluded that 1% hyaluronic acid significantly reduces total surgical time, and incidence of acute spikes may be lower compared to 2% HPMC when used for implantable collamer lens (V4c model).

Comparison of surgical time and IOP spikes with two ophthalmic viscosurgical devices following Visian STAAR (ICL, V4c model) insertion in the immediate postoperative period

PubMed Central

Ganesh, Sri; Brar, Sheetal

2016-01-01

Purpose To compare the effect of two ocular viscosurgical devices (OVDs) on intraocular pressure (IOP) and surgical time in immediate postoperative period after bilateral implantable collamer lens (using the V4c model) implantation. Methods A total of 20 eligible patients were randomized to receive 2% hydroxypropylmethylcellulose (HPMC) in one eye and 1% hyaluronic acid in fellow eye. Time taken for complete removal of OVD and total surgical time were recorded. At the end of surgery, IOP was adjusted between 15 and 20 mmHg in both the eyes. Results Mean time for complete OVD evacuation and total surgical time were significantly higher in the HPMC group (P=0.00). Four eyes in the HPMC group had IOP spike, requiring treatment. IOP values with noncontact tonometry at 1, 2, 4, 24, and 48 hours were not statistically significant (P>0.05) for both the groups. Conclusion The study concluded that 1% hyaluronic acid significantly reduces total surgical time, and incidence of acute spikes may be lower compared to 2% HPMC when used for implantable collamer lens (V4c model). PMID:26869754

New mutations of Saccharomyces cerevisiae that partially relieve both glucose and galactose repression activate the protein kinase Snf1.

PubMed

Rodríguez, Cristina; Sanz, Pascual; Gancedo, Carlos

2003-03-01

We isolated from Saccharomyces cerevisiae two mutants, esc1-1 and ESC3-1, in which genes FBP1, ICL1 or GDH2 were partially derepressed during growth in glucose or galactose. The isolation was done starting with a triple mutant pyc1 pyc2 mth1 unable to grow in glucose-ammonium medium and selecting for mutants able to grow in the non-permissive medium. HXT1 and HXT2 which encode glucose transporters were expressed at high glucose concentrations in both esc1-1 and ESC3-1 mutants, while derepression of invertase at low glucose concentrations was impaired. REG1, cloned as a suppressor of ESC3-1, was not allelic to ESC3-1. Two-hybrid analysis showed an increased interaction of the protein kinase Snf1 with Snf4 in the ESC3-1 mutant; this was not due to mutations in SNF1 or SNF4. ESC3-1 did not bypass the requirement of Snf1 for derepression. We hypothesize that ESC3-1 either facilitates activation of Snf1 or interferes with its glucose-dependent inactivation.

Student Evaluations, Outcomes, and National Licensure Examinations in Radiology Education: A Narrative Review of the Literature.

PubMed

Linaker, Kathleen L

2015-12-01

The purpose of this study was to examine literature on radiological student evaluation and outcome assessments including national board examinations. A review of the literature was performed using relevant key words. Articles were retrieved through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. Of the 4716 unique abstracts reviewed by the author, 54 were found to be relevant to the purpose of this study. Student grade point average correlates with board scores in the nursing, chiropractic, and medical professions. Scores on the chiropractic college admission test and undergraduate grade point average correlate with success in professional college. There is a correlation between board scores and college attended. Board preparation programs do not appear to affect board examination scores. Although evaluations can be effective teaching tools, they are not used by many radiology programs. Some programs have inadequate evaluations and do not allow students to review their evaluations. There are no definitive links between mastery of radiology and specific evaluations, outcomes, or pre-professional/clinical grades. Studies suggest that board examination scores reflect long-term mastery of knowledge rather than short-term memorization of facts.

A serine residue in ClC-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume.

PubMed

Duan, D; Cowley, S; Horowitz, B; Hume, J R

1999-01-01

In many mammalian cells, ClC-3 volume-regulated chloride channels maintain a variety of normal cellular functions during osmotic perturbation. The molecular mechanisms of channel regulation by cell volume, however, are unknown. Since a number of recent studies point to the involvement of protein phosphorylation/dephosphorylation in the control of volume-regulated ionic transport systems, we studied the relationship between channel phosphorylation and volume regulation of ClC-3 channels using site-directed mutagenesis and patch-clamp techniques. In native cardiac cells and when overexpressed in NIH/3T3 cells, ClC-3 channels were opened by cell swelling or inhibition of endogenous PKC, but closed by PKC activation, phosphatase inhibition, or elevation of intracellular Ca2+. Site-specific mutational studies indicate that a serine residue (serine51) within a consensus PKC-phosphorylation site in the intracellular amino terminus of the ClC-3 channel protein represents an important volume sensor of the channel. These results provide direct molecular and pharmacological evidence indicating that channel phosphorylation/dephosphorylation plays a crucial role in the regulation of volume sensitivity of recombinant ClC-3 channels and their native counterpart, ICl.vol.

Biosynthesis and characterization of ZnO nanoparticles using the aqueous leaf extract of Imperata cylindrica L.

NASA Astrophysics Data System (ADS)

Saputra, I. S.; Yulizar, Y.

2017-04-01

ZnO nanoparticles (ZnO NPs) were biosynthesized.The growth was observed by a sol-gel method. ZnO were successfully formed through the reaction of zinc nitrate tetrahydrate Zn(NO3)2.4H2O precursor with aqueous leaf extract of Imperata cylindrica L (ICL). The structural and optical properties of ZnO were investigated. The as-synthesized products were characterized by UV-Visible (UV-Vis), UV diffuse reflectance spectroscopy (UV-DRS), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS). UV-Vis absorption data showed hydrolysis and characteristic of absorption peak at 300 nm of Zn(OH)2. UV-DRS confirmed that ZnO NPs has the indirect band gap at 3.13 eV. FTIR spectrum revealed the functional groups and indicated the presence of protein as the capping and stabilizing agent on the ZnO surface. Powder XRD studies indicated the formation of pure wurtzite hexagonal structure with particle size of 11.9 nm. The detailed morphological and structural characterizations revealed that the synthesized products were hexagonal nanochip.

Increased riboflavin production from activated bleaching earth by a mutant strain of Ashbya gossypii.

PubMed

Tajima, Satoshi; Itoh, Yoko; Sugimoto, Takashi; Kato, Tatsuya; Park, Enoch Y

2009-10-01

The production of riboflavin from vegetable oil was increased using a mutant strain of Ashbya gossypii. This mutant was generated by treating the wild-type strain with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Riboflavin production was 10-fold higher in the mutant compared to the wild-type strain. The specific intracellular catalase activity after 3 d of culture was 6-fold higher in the mutant than in the wild-type strain. For the mutant, riboflavin production in the presence of 40 mM hydrogen peroxide was 16% less than that in the absence of hydrogen peroxide, whereas it was 56% less for the wild-type strain. The isocitrate lyase (ICL) activity of the mutant was 0.26 mU/mg of protein during the active riboflavin production phase, which was 2.6-fold higher than the wild-type strain. These data indicate that the mutant utilizes the carbon flux from the TCA cycle to the glyoxylate cycle more efficiently than the wild-type strain, resulting in enhanced riboflavin production. This novel mutant has the potential to be of use for industrial-scale riboflavin production from waste-activated bleaching earth (ABE), thereby transforming a useless material into a valuable bioproduct.

Ultrafast nuclear dynamics in halomethanes studied with time-resolved Coulomb explosion imaging and channel-selective Fourier spectroscopy

NASA Astrophysics Data System (ADS)

Malakar, Y.; Kaderiya, B.; Pearson, W. L.; Ziaee, F.; Kanaka Raju, P.; Zohrabi, M.; Jensen, K.; Rajput, J.; Ben-Itzhak, I.; Rolles, D.; Rudenko, A.

2016-05-01

Halomethanes have recently attracted considerable attention since they often serve as prototype systems for laser-controlled chemistry (e.g., selective bond breaking or concerted elimination reactions), and are important molecules in atmospheric chemistry. Here we combine a femtosecond laser pump-probe setup with coincident 3D ion momentum imaging apparatus to study strong-field induced nuclear dynamics in methane and several of its halogenated derivatives (CH3 I, CH2 I2, CH2 ICl). We apply a time-resolved Coulomb explosion imaging technique to map the nuclear motion on both, bound and continuum potential surfaces, disentangle different fragmentation pathways and, for halogenated molecules, observe clear signatures of vibrational wave packets in neutral or ionized states. Channel-selective and kinetic-energy resolved Fourier analysis of these data allows for unique identification of different electronic states and vibrational modes responsible for a particular structure. Supported by the Chemical Sciences, Geosciences, and Biosciences Division, Office of Basic Energy Sciences, Office of Science, U. S. DOE. K. R. P. and W. L. P. supported by NSF Award No. IIA-143049. K.J. supported by the NSF-REU Grant No. PHYS-1461251.

Sensitive detection of formaldehyde using an interband cascade laser near 3.6 μm

DOE PAGES

Ren, Wei; Luo, Longqiang; Tittel, Frank K.

2015-12-31

Here, we report the development of a formaldehyde (H 2CO) trace gas sensor using a continuous wave (CW), thermoelectrically-cooled (TEC), distributed-feedback interband cascade laser (DFB-ICL) at 3.6 μm. Wavelength modulation spectroscopy was used to detect the second harmonic spectra of a strong H 2CO absorption feature centered at 2778.5 cm -1 (3599 nm) in its ν 1 fundamental vibrational band. A compact and novel multipass cell (7.6-cm physical length and 32-ml sampling volume) was implemented to achieve an effective optical path length of 3.75 m. A minimum detection limit of 6 parts per billion (ppb) at an optimum gas pressuremore » of 200 Torr was achieved with a 1-s data acquisition time. An Allan-Werle deviation analysis was performed to investigate the long-term stability of the sensor system and a 1.5 ppb minimum detectable concentration could be achieved by averaging up to 140 s. Absorption interference eeffects from atmospheric H 2O (2%) and CH 4(5 ppm) were also analyzed in this work and proved to be insignificant for the current sensor configuration.« less

Cervical Spine Involvement in Mild Traumatic Brain Injury: A Review

PubMed Central

Morin, Michael; Langevin, Pierre

2016-01-01

Background. There is a lack of scientific evidence in the literature on the involvement of the cervical spine in mTBI; however, its involvement is clinically accepted. Objective. This paper reviews evidence for the involvement of the cervical spine in mTBI symptoms, the mechanisms of injury, and the efficacy of therapy for cervical spine with concussion-related symptoms. Methods. A keyword search was conducted on PubMed, ICL, SportDiscus, PEDro, CINAHL, and Cochrane Library databases for articles published since 1990. The reference lists of articles meeting the criteria (original data articles, literature reviews, and clinical guidelines) were also searched in the same databases. Results. 4,854 records were screened and 43 articles were retained. Those articles were used to describe different subjects such as mTBI's signs and symptoms, mechanisms of injury, and treatments of the cervical spine. Conclusions. The hypothesis of cervical spine involvement in post-mTBI symptoms and in PCS (postconcussion syndrome) is supported by increasing evidence and is widely accepted clinically. For the management and treatment of mTBIs, few articles were available in the literature, and relevant studies showed interesting results about manual therapy and exercises as efficient tools for health care practitioners. PMID:27529079

Sensitive detection of formaldehyde using an interband cascade laser near 3.6 μm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ren, Wei; Luo, Longqiang; Tittel, Frank K.

Here, we report the development of a formaldehyde (H 2CO) trace gas sensor using a continuous wave (CW), thermoelectrically-cooled (TEC), distributed-feedback interband cascade laser (DFB-ICL) at 3.6 μm. Wavelength modulation spectroscopy was used to detect the second harmonic spectra of a strong H 2CO absorption feature centered at 2778.5 cm -1 (3599 nm) in its ν 1 fundamental vibrational band. A compact and novel multipass cell (7.6-cm physical length and 32-ml sampling volume) was implemented to achieve an effective optical path length of 3.75 m. A minimum detection limit of 6 parts per billion (ppb) at an optimum gas pressuremore » of 200 Torr was achieved with a 1-s data acquisition time. An Allan-Werle deviation analysis was performed to investigate the long-term stability of the sensor system and a 1.5 ppb minimum detectable concentration could be achieved by averaging up to 140 s. Absorption interference eeffects from atmospheric H 2O (2%) and CH 4(5 ppm) were also analyzed in this work and proved to be insignificant for the current sensor configuration.« less

Cascade laser applications: trends and challenges

NASA Astrophysics Data System (ADS)

d'Humières, B.; Margoto, Éric; Fazilleau, Yves

2016-03-01

When analyses need rapid measurements, cost effective monitoring and miniaturization, tunable semiconductor lasers can be very good sources. Indeed, applications like on-field environmental gas analysis or in-line industrial process control are becoming available thanks to the advantage of tunable semiconductor lasers. Advances in cascade lasers (CL) are revolutionizing Mid-IR spectroscopy with two alternatives: interband cascade lasers (ICL) in the 3-6μm spectrum and quantum cascade lasers (QCL), with more power from 3 to 300μm. The market is getting mature with strong players for driving applications like industry, environment, life science or transports. CL are not the only Mid-IR laser source. In fact, a strong competition is now taking place with other technologies like: OPO, VCSEL, Solid State lasers, Gas, SC Infrared or fiber lasers. In other words, CL have to conquer a share of the Mid-IR application market. Our study is a market analysis of CL technologies and their applications. It shows that improvements of components performance, along with the progress of infrared laser spectroscopy will drive the CL market growth. We compare CL technologies with other Mid-IR sources and estimate their share in each application market.

Cyclic GMP-dependent but G-kinase-independent inhibition of Ca2+-dependent Cl− currents by NO donors in cat tracheal smooth muscle

PubMed Central

Waniishi, Yoshiki; Inoue, Ryuji; Morita, Hiromitsu; Teramoto, Noriyoshi; Abe, Kihachiro; Ito, Yushi

1998-01-01

The effects of NO donors on Ca2+-dependent Cl− currents (ICl(Ca)) were investigated in freshly isolated cat tracheal myocytes using the whole-cell patch clamp technique. With nystatin-perforated whole-cell recording, carbachol (CCh, ≥ 1 μm) induced a transient inward current (ICCh) with a reversal potential of about -20 mV. Activation of ICCh probably occurred through the M3 muscarinic receptor, since nanomolar concentrations of 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP) greatly inhibited this current, while 11-(2-(diethylamino)methyl)-1-piperidinylacetyl)-5,11-dihydro-6H-pyrido (2,3β) (1,4)benzodiazepine-6-one (AF-DX 116) or pirenzepine at concentrations of up to 1 μm were almost ineffective. Chloride channel/transporter blockers such as DIDS (100 μm), anthracene-9-carboxylic acid (9-AC, 100 μm) and niflumic acid (100 μm) greatly inhibited ICCh, but cation channel blockers, such as nifedipine (10 μm), Zn2+ (500 μm) or Gd3+ (500 μm), were without effect. Activation of ICCh was strongly attenuated by pretreatment with ryanodine (4 μm) plus caffeine (10 mM). Addition of neomycin (1 mM) into the bath or inclusion of heparin (3 mg ml−1) in the pipette abolished a substantial part of ICCh. These results suggest that ICCh is ICl(Ca), which is activated by inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release. The nitric oxide donor S-nitroso-N-acetyl penicillamine (SNAP) reduced the amplitude of ICCh dose dependently (IC50, ≈10 μm). Similar inhibition was also exerted by other types of NO donor such as glyceryl trinitrate (GTN) and (±)-E-methyl-2-(E-hydroxyimitol)-5-nitro-6-methoxy-3-hexeneamide (NO-R). SNAP-induced ICCh inhibition was effectively antagonized by Methylene Blue (1-100 nM), and mimicked by dibutyryl cGMP (db-cGMP) (0.5-1 mM), whereas two structurally distinct types of cGMP-dependent (G)-kinase inhibitor, N-(2-aminoethyl)-5-isoquinilinesulphonamide (H-8, 2.5 μm) and KT5823 (1 μm), failed to counteract the inhibitory effects of SNAP or db-cGMP. Another G-kinase-specific inhibitor Rp-8-(para-chlorophenylthio)guanosine-3′,5′-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS; 1 μm) itself caused a marked reduction in ICCh. SNAP (100 μm) or db-cGMP (100 μm) exhibited no inhibitory actions, when caffeine (10 mM) or photolytically released IP3 were used instead of CCh to activate the inward current. These results suggest that inhibition of ICCh by NO donors involves a cGMP-dependent but G-kinase-independent mechanism, which may operate at a site(s) between the muscarinic (M3) and IP3 receptors. PMID:9714855

Structural and biophysical properties of h-FANCI ARM repeat protein.

PubMed

Siddiqui, Mohd Quadir; Choudhary, Rajan Kumar; Thapa, Pankaj; Kulkarni, Neha; Rajpurohit, Yogendra S; Misra, Hari S; Gadewal, Nikhil; Kumar, Satish; Hasan, Syed K; Varma, Ashok K

2017-11-01

Fanconi anemia complementation groups - I (FANCI) protein facilitates DNA ICL (Inter-Cross-link) repair and plays a crucial role in genomic integrity. FANCI is a 1328 amino acids protein which contains armadillo (ARM) repeats and EDGE motif at the C-terminus. ARM repeats are functionally diverse and evolutionarily conserved domain that plays a pivotal role in protein-protein and protein-DNA interactions. Considering the importance of ARM repeats, we have explored comprehensive in silico and in vitro approach to examine folding pattern. Size exclusion chromatography, dynamic light scattering (DLS) and glutaraldehyde crosslinking studies suggest that FANCI ARM repeat exist as monomer as well as in oligomeric forms. Circular dichroism (CD) and fluorescence spectroscopy results demonstrate that protein has predominantly α- helices and well-folded tertiary structure. DNA binding was analysed using electrophoretic mobility shift assay by autoradiography. Temperature-dependent CD, Fluorescence spectroscopy and DLS studies concluded that protein unfolds and start forming oligomer from 30°C. The existence of stable portion within FANCI ARM repeat was examined using limited proteolysis and mass spectrometry. The normal mode analysis, molecular dynamics and principal component analysis demonstrated that helix-turn-helix (HTH) motif present in ARM repeat is highly dynamic and has anti-correlated motion. Furthermore, FANCI ARM repeat has HTH structural motif which binds to double-stranded DNA.

BRCA1 interacts directly with the Fanconi anemia protein FANCA.

PubMed

Folias, Alexandra; Matkovic, Mara; Bruun, Donald; Reid, Sonja; Hejna, James; Grompe, Markus; D'Andrea, Alan; Moses, Robb

2002-10-01

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by skeletal defects, anemia, chromosomal instability and increased risk of leukemia. At the cellular level FA is characterized by increased sensitivity to agents forming interstrand crosslinks (ICL) in DNA. Six FA genes have been cloned and interactions among individual FANC proteins have been found. The FANCD2 protein co-localizes in nuclear foci with the BRCA1 protein following DNA damage and during S-phase, requiring the FANCA, C, E and G proteins to do so. This finding may reflect a direct role for the BRCA1 protein in double strand break (DSB) repair and interaction with the FANC proteins. Therefore interactions between BRCA1 and the FANC proteins were investigated. Among the known FANC proteins, we find evidence for direct interaction only between the FANCA protein and BRCA1. The evidence rests on three different tests: yeast two-hybrid analysis, coimmunoprecipitation from in vitro synthesis, and coimmunoprecipitation from cell extracts. The amino terminal portion of FANCA and the central part (aa 740-1083) of BRCA1 contain the sites of interaction. The interaction does not depend on DNA damage, thus FANCA and BRCA1 are constitutively interacting. The demonstrated interaction directly connects BRCA1 to the FA pathway of DNA repair.

Mutants of Saccharomyces Cerevisiae with Defects in Acetate Metabolism: Isolation and Characterization of Acn(-) Mutants

PubMed Central

McCammon, M. T.

1996-01-01

The two carbon compounds, ethanol and acetate, can be oxidatively metabolized as well as assimilated into carbohydrate in the yeast Saccharomyces cerevisiae. The distribution of acetate metabolic enzymes among several cellular compartments, mitochondria, peroxisomes, and cytoplasm makes it an intriguing system to study complex metabolic interactions. To investigate the complex process of carbon catabolism and assimilation, mutants unable to grow on acetate were isolated. One hundred five Acn(-) (``ACetate Nonutilizing'') mutants were sorted into 21 complementation groups with an additional 20 single mutants. Five of the groups have defects in TCA cycle enzymes: MDH1, CIT1, ACO1, IDH1, and IDH2. A defect in RTG2, involved in the retrograde communication between the mitochondrion and the nucleus, was also identified. Four genes encode enzymes of the glyoxylate cycle and gluconeogenesis: ICL1, MLS1, MDH2, and PCK1. Five other genes appear to be defective in regulating metabolic activity since elevated levels of enzymes in several metabolic pathways, including the glyoxylate cycle, gluconeogenesis, and acetyl-CoA metabolism, were detected in these mutants: ACN8, ACN9, ACN17, ACN18, and ACN42. In summary, this analysis has identified at least 22 and as many as 41 different genes involved in acetate metabolism. PMID:8878673

Flow visualization of a non-contact transport device by Coanda effect

NASA Astrophysics Data System (ADS)

Iki, Norihiko; Abe, Hiroyuki; Okada, Takashi

2014-08-01

AIST proposes new technology of non-contact transport device utilizing Coanda effect. A proposed non-contact transport device has a cylindrical body and circular slit for air. The air flow around non-contact device is turbulent and its flow pattern depends on the injection condition. Therefore we tried visualization of the air flow around non -contact device as the first step of PIV measurement. Several tracer particles were tried such as TiO2 particles, water droplets, potatoes starch, rice starch, corn starch. Hot-wire anemometer is employed to velocity measurement. TiO2 particles deposit inside of a slit and clogging of a slit occurs frequently. Potato starch particles do not clog a slit but they are too heavy to trace slow flow area. Water droplets by ultrasonic atomization also deposit inside of slit but they are useful to visualize flow pattern around a non-contact transport device by being supplied from circumference. Coanda effect of proposed non-contact transport device was confirmed and injected air flow pattern switches by a work. Air flow around non-contact trance port device is turbulent and its velocity range is wide. Therefore flow measurement by tracer part icle has traceability issue. Suitable tracer and exposure condition depends on target area.

Student Evaluations, Outcomes, and National Licensure Examinations in Radiology Education: A Narrative Review of the Literature

PubMed Central

Linaker, Kathleen L.

2015-01-01

Objective The purpose of this study was to examine literature on radiological student evaluation and outcome assessments including national board examinations. Methods A review of the literature was performed using relevant key words. Articles were retrieved through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. Results Of the 4716 unique abstracts reviewed by the author, 54 were found to be relevant to the purpose of this study. Student grade point average correlates with board scores in the nursing, chiropractic, and medical professions. Scores on the chiropractic college admission test and undergraduate grade point average correlate with success in professional college. There is a correlation between board scores and college attended. Board preparation programs do not appear to affect board examination scores. Conclusion Although evaluations can be effective teaching tools, they are not used by many radiology programs. Some programs have inadequate evaluations and do not allow students to review their evaluations. There are no definitive links between mastery of radiology and specific evaluations, outcomes, or pre-professional/clinical grades. Studies suggest that board examination scores reflect long-term mastery of knowledge rather than short-term memorization of facts. PMID:26770174

Structural signatures of DRD4 mutants revealed using molecular dynamics simulations: Implications for drug targeting.

PubMed

Jatana, Nidhi; Thukral, Lipi; Latha, N

2016-01-01

Human Dopamine Receptor D4 (DRD4) orchestrates several neurological functions and represents a target for many psychological disorders. Here, we examined two rare variants in DRD4; V194G and R237L, which elicit functional alterations leading to disruption of ligand binding and G protein coupling, respectively. Using atomistic molecular dynamics (MD) simulations, we provide in-depth analysis to reveal structural signatures of wild and mutant complexes with their bound agonist and antagonist ligands. We constructed intra-protein network graphs to discriminate the global conformational changes induced by mutations. The simulations also allowed us to elucidate the local side-chain dynamical variations in ligand-bound mutant receptors. The data suggest that the mutation in transmembrane V (V194G) drastically disrupts the organization of ligand binding site and causes disorder in the native helical arrangement. Interestingly, the R237L mutation leads to significant rewiring of side-chain contacts in the intracellular loop 3 (site of mutation) and also affects the distant transmembrane topology. Additionally, these mutations lead to compact ICL3 region compared to the wild type, indicating that the receptor would be inaccessible for G protein coupling. Our findings thus reveal unreported structural determinants of the mutated DRD4 receptor and provide a robust framework for design of effective novel drugs.

Methylopila helvetica sp. nov. and Methylobacterium dichloromethanicum sp. nov.--novel aerobic facultatively methylotrophic bacteria utilizing dichloromethane.

PubMed

Doronina, N V; Trotsenko, Y A; Tourova, T P; Kuznetsov, B B; Leisinger, T

2000-06-01

Eight strains of Gram-negative, aerobic, asporogenous, neutrophilic, mesophilic, facultatively methylotrophic bacteria are taxonomically described. These icl- serine pathway methylobacteria utilize dichloromethane, methanol and methylamine as well as a variety of polycarbon compounds as the carbon and energy source. The major cellular fatty acids of the non-pigmented strains DM1, DM3, and DM5 to DM9 are C18:1, C16:0, C18:0, Ccy19:0 and that of the pink-pigmented strain DM4 is C18:1. The main quinone of all the strains is Q-10. The non-pigmented strains have similar phenotypic properties and a high level of DNA-DNA relatedness (81-98%) as determined by hybridization. All strains belong to the alpha-subgroup of the alpha-Proteobacteria. 16S rDNA sequence analysis led to the classification of these dichloromethane-utilizers in the genus Methylopila as a new species - Methylopila helvetica sp.nov. with the type strain DM9 (=VKM B-2189). The pink-pigmented strain DM4 belongs to the genus Methylobacterium but differs from the known members of this genus by some phenotypic properties, DNA-DNA relatedness (14-57%) and 16S rDNA sequence. Strain DM4 is named Methylobacterium dichloromethanicum sp. nov. (VKM B-2191 = DSMZ 6343).

A graphical user interface for infant ERP analysis.

PubMed

Kaatiala, Jussi; Yrttiaho, Santeri; Forssman, Linda; Perdue, Katherine; Leppänen, Jukka

2014-09-01

Recording of event-related potentials (ERPs) is one of the best-suited technologies for examining brain function in human infants. Yet the existing software packages are not optimized for the unique requirements of analyzing artifact-prone ERP data from infants. We developed a new graphical user interface that enables an efficient implementation of a two-stage approach to the analysis of infant ERPs. In the first stage, video records of infant behavior are synchronized with ERPs at the level of individual trials to reject epochs with noncompliant behavior and other artifacts. In the second stage, the interface calls MATLAB and EEGLAB (Delorme & Makeig, Journal of Neuroscience Methods 134(1):9-21, 2004) functions for further preprocessing of the ERP signal itself (i.e., filtering, artifact removal, interpolation, and rereferencing). Finally, methods are included for data visualization and analysis by using bootstrapped group averages. Analyses of simulated and real EEG data demonstrated that the proposed approach can be effectively used to establish task compliance, remove various types of artifacts, and perform representative visualizations and statistical comparisons of ERPs. The interface is available for download from http://www.uta.fi/med/icl/methods/eeg.html in a format that is widely applicable to ERP studies with special populations and open for further editing by users.

Radiology Undergraduate and Resident Curricula: A Narrative Review of the Literature

PubMed Central

Linaker, Kathleen L.

2015-01-01

Objective The purpose of this study was to examine the literature regarding radiology curricula for both undergraduates and residents. Methods A review of the literature was performed using relevant key words. Articles were retrieved through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. Results Of the 4716 unique abstracts reviewed by the author, 142 were found to be relevant to the purpose of this study. Undergraduate radiology education, radiology curriculum, and radiology pedagogy vary widely between disciplines and between colleges within disciplines. Formal radiology education is not taught at all medical programs and little radiology training is incorporated into non-radiology residencies. This results in some medical graduates not being taught how to interpret basic radiology images and not learning contraindications and indications for ordering diagnostic imaging tests. There are no definitive studies examining how to incorporate radiology into the curriculum, how to teach radiology to either undergraduates or residents, or how to assess this clinical competency. Conclusions This review shows that radiology education is perceived to be important in undergraduate and residency programs. However, some programs do not include radiology training, thus graduates from those programs do not learn radiology essentials. PMID:26770172

Electrotherapy for neck pain.

PubMed

Kroeling, Peter; Gross, Anita; Goldsmith, Charles H; Burnie, Stephen J; Haines, Ted; Graham, Nadine; Brant, Aron

2009-10-07

Neck pain is common, disabling and costly. The effectiveness of electrotherapy as a physiotherapeutic option remains unclear. This update replaces our 2005 Cochrane review on this topic. To assess whether electrotherapy improves pain, disability, patient satisfaction, and global perceived effect in adults with neck pain. Computer-assisted searches of: CENTRAL, MEDLINE, EMBASE, MANTIS, CINAHL, and ICL, without language restrictions, from their beginning to December 2008; handsearched relevant conference proceedings; consulted content experts. Randomised controlled trials in any language, investigating the effects of electrotherapy, used primarily as unimodal treatment for neck pain. Quasi-RCTs and controlled clinical trials were excluded. At least two authors independently conducted citation identification, study selection, data abstraction, and risk of bias assessment. We were unable to statistically pool any of the results, but assessed the quality of the evidence using an adapted GRADE approach. Eighteen small trials (1043 people with neck pain) with 23 comparisons were included. Analysis was limited by trials of varied quality, heterogeneous treatment subtypes and conflicting results. The main findings for reduction of neck pain by treatment with electrotherapeutic modalities are:Very low quality evidence that pulsed electromagnetic field therapy (PEMF), repetitive magnetic stimulation (rMS) and transcutaneous electrical nerve stimulation (TENS) are more effective than placebo.Low quality evidence that permanent magnets (necklace) are not more effective than placebo.Very low quality evidence that modulated galvanic current, iontophoresis and electric muscle stimulation (EMS) are not more effective than placebo.There were only four trials that reported on other outcomes such as function and global perceived effects, but none were of clinical importance. We cannot make any definite statements on the efficacy and clinical usefulness of electrotherapy modalities for neck pain. Since the quality of evidence is low or very low, we are uncertain about the estimate of the effect. Further research is very likely to change both the estimate of effect and our confidence in the results. Current evidence for PEMF, rMS, and TENS shows that these modalities might be more effective than placebo but not other interventions. Funding bias should be considered, especially in PEMF studies. Galvanic current, iontophoresis, electric muscle stimulation(EMS), and static magnetic field did not reduce pain or disability. Future trials on these interventions should have larger patient samples and include more precise standardization and description of all treatment characteristics.

Unit and internal chain profile of African rice (Oryza glaberrima) amylopectin.

PubMed

Gayin, Joseph; Abdel-Aal, El-Sayed M; Manful, John; Bertoft, Eric

2016-02-10

High-performance anion-exchange chromatography was used to study the unit chain profiles of amylopectins and their φ,β-limit dextrins from two African rice (Oryza glaberrima) accessions-TOG 12440 and IRGC 103759. The samples were compared with two Asian rice (Oryza sativa) samples (cv Koshihikari and cv WITA 4) and one O. sativa × O. glaberrima cross (NERICA 4). The ratio of short:long chains ranged between 12.1 and 13.8, and the ratio of A:B-chains was ∼ 1.0 in all samples. A significant difference was observed in the distribution of internal chains with regards to the proportion of short "fingerprint" B-chains (Bfp-chains), which in the φ,β-limit dextrins have a degree of polymerization (DP) 3-7. The African rice starches and NERICA 4 had higher levels of Bfp-chains, but the major group of short B-chains (DP 8-25) was similar to that of the Asian rice samples. The average chain length (CL), internal chain length (ICL), and total internal chain length (TICL) were similar in all samples. However, the external chain length (ECL) was longer in the African rice samples and NERICA 4. ECL correlated positively and significantly (p<0.05) with gelatinization transition temperatures and enthalpy suggesting differences between the two rice types in cooking properties. Copyright © 2015 Elsevier Ltd. All rights reserved.

Laser spectrometer for CO2 clumped isotope analysis

NASA Astrophysics Data System (ADS)

Prokhorov, Ivan; Kluge, Tobias; Janssen, Christof

2017-04-01

Carbon dioxide clumped isotope thermometry has proven to be a reliable method for biogeochemical and atmospheric research. We present a new laser spectroscopic instrument for doubly-substituted isotopologues analysis. In contrast to a conventional isotope ratio mass spectrometry (IRMS), tunable laser direct absorption spectroscopy (TLDAS) has the advantage of isotopologue-specific determination free of isobaric interferences. Tunable infrared laser based spectrometer for clumped isotope analysis is being developed in collaboration between Heidelberg University, Germany, and LERMA-IPSL, CNRS, France. The instrument employs two continuous intraband cascade lasers (ICL) tuned at 4439 and 4329 nm. The spectral windows covered by the lasers contain absorption lines of the six most abundant CO2 isotopologues, including the two doubly substituted species 16O13C18O and 16O13C17O, and all singly substituted isotopologues with 13C, 18O and 17O. A Herriott-type multi-pass cell provides two different absorption pathlengths to compensate the abundance difference between singly- and doubly-substituted isotopologues. We have reached the sub-permill precision required for clumped isotope measurements within the integration time of several seconds. The test version of the instrument demonstrates a performance comparable to state of the art IRMS. We highlight the following features of the instrument that are strong advantages compared to conventional mass spectrometry: measurement cycle in the minute range, simplified sample preparation routine, table-top layout with a potential for in-situ applications.

Pedagogical Approaches to Diagnostic Imaging Education: A Narrative Review of the Literature

PubMed Central

Linaker, Kathleen L.

2015-01-01

Objective The purpose of this study was to examine literature on how radiology is taught and learned by both radiology residents and undergraduates in the health professions. Methods A review of the literature was performed using relevant key words. Articles were retrieved through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. Results Of the 4716 unique abstracts reviewed by the author, 91 were found to be relevant to the purpose of this study. The literature retrieved reported pedagogical approaches to teaching radiology including the following: problem solving, technology as teacher, independent learning tools, visiting lectureships, case based teaching, and conferences. There was some exploration of the relative effectiveness of educational formats. Suggestions for future research identify 7 areas of relative consistency. Conclusion Radiology is a clinical skill that requires integration science, clinical information, clinical experiences, and information recorded on diagnostic imaging studies. The research in this area focuses on problem solving, the use of algorithm/scripts, introducing uncertainty in clinical scenarios, incorporating technology in learning environments, active learning techniques, and methods of independent learning. Although the literature in this area is still in its infancy, the research examining the relative effectiveness of these various educational formats is often contradictory, suggesting that this is a complex area of study with numerous factors influencing student learning. PMID:26770173

Topochemical conversion of a dense metal–organic framework from a crystalline insulator to an amorphous semiconductor† †Electronic supplementary information (ESI) available: PXRD, impedance, TGA, IR, XPS, PDF, ESR, and CIF files. CCDC 1018776–1018778. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4sc03295k Click here for additional data file.

PubMed Central

Hamoudi, H.; Suga, T.; Bennett, T. D.; Cairns, A. B.

2015-01-01

The topochemical conversion of a dense, insulating metal–organic framework (MOF) into a semiconducting amorphous MOF is described. Treatment of single crystals of copper(i) chloride trithiocyanurate, CuICl(ttcH3) (ttcH3 = trithiocyanuric acid), 1, in aqueous ammonia solution yields monoliths of amorphous CuI 1.8(ttc)0.6(ttcH3)0.4, 3. The treatment changes the transparent orange crystals of 1 into shiny black monoliths of 3 with retention of morphology, and moreover increases the electrical conductivity from insulating to semiconducting (conductivity of 3 ranges from 4.2 × 10–11 S cm–1 at 20 °C to 7.6 × 10–9 S cm–1 at 140 °C; activation energy = 0.59 eV; optical band gap = 0.6 eV). The structure and properties of the amorphous conductor are fully characterized by AC impedance spectroscopy, X-ray photoelectron spectroscopy, X-ray pair distribution function analysis, infrared spectroscopy, diffuse reflectance spectroscopy, electron spin resonance spectroscopy, elemental analysis, thermogravimetric analysis, and theoretical calculations. PMID:29560235

RCS2 J232727.6-020437: An efficient cosmic telescope at Z = 0.6986

DOE PAGES

Hoag, A.; Bradac, M.; Huang, K. H.; ...

2015-10-27

Here, we present a detailed gravitational lens model of the galaxy cluster RCS2 J232727.6-020437. Due to cosmological dimming of cluster members and ICL, its high redshift (z=0.6986) makes it ideal for studying background galaxies. Using new ACS and WFC3/IR HST data, we identify 16 multiple images. From MOSFIRE follow up, we identify a strong emission line in the spectrum of one multiple image, likely confirming the redshift of that system to z=2.083. With a highly magnified (μ ≳ 2) source plane area of ~ 0.7 arcmin 2 at z = 7, RCS2 J232727.6-020437 has a lensing efficiency comparable to themore » Hubble Frontier Fields clusters. We discover four highly magnified z ~ 7 candidate Lyman-break galaxies behind the cluster, one of which may be multiply-imaged. Correcting for magnification, we find that all four galaxies are fainter than 0.5L *. One candidate is detected at >10σ in both Spitzer/IRAC [3.6] and [4.5] channels. A spectroscopic follow-up with MOSFIRE does not result in the detection of the Lyman-alpha emission line from any of the four candidates. From the MOSFIRE spectra we place median upper limits on the Lyman-alpha flux of 5 – 14 × 10 –19 ergs –1cm –2 (5σ).« less

A minimal threshold of FANCJ helicase activity is required for its response to replication stress or double-strand break repair.

PubMed

Bharti, Sanjay Kumar; Sommers, Joshua A; Awate, Sanket; Bellani, Marina A; Khan, Irfan; Bradley, Lynda; King, Graeme A; Seol, Yeonee; Vidhyasagar, Venkatasubramanian; Wu, Yuliang; Abe, Takuye; Kobayashi, Koji; Shin-Ya, Kazuo; Kitao, Hiroyuki; Wold, Marc S; Branzei, Dana; Neuman, Keir C; Brosh, Robert M

2018-05-21

Fanconi Anemia (FA) is characterized by bone marrow failure, congenital abnormalities, and cancer. Of over 20 FA-linked genes, FANCJ uniquely encodes a DNA helicase and mutations are also associated with breast and ovarian cancer. fancj-/- cells are sensitive to DNA interstrand cross-linking (ICL) and replication fork stalling drugs. We delineated the molecular defects of two FA patient-derived FANCJ helicase domain mutations. FANCJ-R707C was compromised in dimerization and helicase processivity, whereas DNA unwinding by FANCJ-H396D was barely detectable. DNA binding and ATP hydrolysis was defective for both FANCJ-R707C and FANCJ-H396D, the latter showing greater reduction. Expression of FANCJ-R707C or FANCJ-H396D in fancj-/- cells failed to rescue cisplatin or mitomycin sensitivity. Live-cell imaging demonstrated a significantly compromised recruitment of FANCJ-R707C to laser-induced DNA damage. However, FANCJ-R707C expressed in fancj-/- cells conferred resistance to the DNA polymerase inhibitor aphidicolin, G-quadruplex ligand telomestatin, or DNA strand-breaker bleomycin, whereas FANCJ-H396D failed. Thus, a minimal threshold of FANCJ catalytic activity is required to overcome replication stress induced by aphidicolin or telomestatin, or to repair bleomycin-induced DNA breakage. These findings have implications for therapeutic strategies relying on DNA cross-link sensitivity or heightened replication stress characteristic of cancer cells.

Progress report: Continued development of an integrated sounding system in support of the DOE/ARM experimental program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Edgeworth R. Westwater; Kenneth S. Gage; Yong Han

1996-09-06

From January 6 to February 28, 1993, the second phase of the Prototype Radiation Observation Experiment (PROBE) was conducted in Kavieng, Papua New Guinea. Data taken during PROBE included frequent radiosondes, 915 MHz Wind profiler/Radio Acoustic Sounding System (RASS) observations of winds and temperatures, and lidar measurements of cloud-base heights. In addition, a dual-channel Microwave Water Substance Radiometer (MWSR) at 23.87 and 31.65 GHz and a Fourier Transform Infrared Radiometer (FTIR) were operated. The FTIR operated between 500 and 2000 cm{sup -1} and measured some of the first high spectral resolution (1 cm{sup -1}) radiation data taken in the tropics.more » The microwave radiometer provided continuous measurements with 30-second resolution of precipitable water vapor (PWV) and integrated cloud liquid (ICL), the RASS measured virtual temperature profiles every 30 minutes, and the cloud lidar provided episodic measurements of clouds every minute. The RASS, MWSR, and FTIR data taken during PROBE were compared with radiosonde data. Broadband longwave and shortwave irradiance data and lidar data were used to identify the presence of cirrus clouds and clear conditions. Comparisons were made between measured and calculated radiance during clear conditions, using radiosonde data as input to a Line-By-Line Radiative Transfer Model. Comparisons of RASS-measured virtual temperature with radiosonde data revealed a significant cold bias below 500 m.« less

Iodide, bromide, and ammonium in hydraulic fracturing and oil and gas wastewaters: environmental implications.

PubMed

Harkness, Jennifer S; Dwyer, Gary S; Warner, Nathaniel R; Parker, Kimberly M; Mitch, William A; Vengosh, Avner

2015-02-03

The expansion of unconventional shale gas and hydraulic fracturing has increased the volume of the oil and gas wastewater (OGW) generated in the U.S. Here we demonstrate that OGW from Marcellus and Fayetteville hydraulic fracturing flowback fluids and Appalachian conventional produced waters is characterized by high chloride, bromide, iodide (up to 56 mg/L), and ammonium (up to 420 mg/L). Br/Cl ratios were consistent for all Appalachian brines, which reflect an origin from a common parent brine, while the I/Cl and NH4/Cl ratios varied among brines from different geological formations, reflecting geogenic processes. There were no differences in halides and ammonium concentrations between OGW originating from hydraulic fracturing and conventional oil and gas operations. Analysis of discharged effluents from three brine treatment sites in Pennsylvania and a spill site in West Virginia show elevated levels of halides (iodide up to 28 mg/L) and ammonium (12 to 106 mg/L) that mimic the composition of OGW and mix conservatively in downstream surface waters. Bromide, iodide, and ammonium in surface waters can impact stream ecosystems and promote the formation of toxic brominated-, iodinated-, and nitrogen disinfection byproducts during chlorination at downstream drinking water treatment plants. Our findings indicate that discharge and accidental spills of OGW to waterways pose risks to both human health and the environment.

Innovative mid-infrared detector concepts

NASA Astrophysics Data System (ADS)

Höfling, Sven; Pfenning, Andreas; Weih, Robert; Ratajczak, Albert; Hartmann, Fabian; Knebl, Georg; Kamp, Martin; Worschech, Lukas

2016-09-01

Gas sensing is a key technology with applications in various industrial, medical and environmental areas. Optical detection mechanisms allow for a highly selective, contactless and fast detection. For this purpose, rotational-vibrational absorption bands within the mid infrared (MIR) spectral region are exploited and probed with appropriate light sources. During the past years, the development of novel laser concepts such as interband cascade lasers (ICLs) and quantum cascade lasers (QCLs) has driven a continuous optimization of MIR laser sources. On the other hand side, there has been relatively little progress on detectors in this wavelength range. Here, we study two novel and promising GaSb-based detector concepts: Interband cascade detectors (ICD) and resonant tunneling diode (RTD) photodetectors. ICDs are a promising approach towards highly sensitive room temperature detection of MIR radiation. They make use of the cascading scheme that is enabled by the broken gap alignment of the two binaries GaSb and InAs. The interband transition in GaSb/InAs-superlattices (SL) allows for normal incidence detection. The cut-off wavelength, which determines the low energy detection limit, can be engineered via the SL period. RTD photodetectors act as low noise and high speed amplifiers of small optically generated electrical signals. In contrast to avalanche photodiodes, where the gain originates from multiplication due to impact ionization, in RTD photodetectors a large tunneling current is modulated via Coulomb interaction by the presence of photogenerated minority charge carriers. For both detector concepts, first devices operational at room temperature have been realized.

Patient-reported outcomes of deferasirox (Exjade, ICL670) versus deferoxamine in sickle cell disease patients with transfusional hemosiderosis. Substudy of a randomized open-label phase II trial.

PubMed

Vichinsky, Elliott; Pakbaz, Zahra; Onyekwere, Onyinye; Porter, John; Swerdlow, Paul; Coates, Thomas; Lane, Peter; Files, Beatrice; Mueller, Brigitta U; Coïc, Lena; Forni, Gian Luca; Fischer, Roland; Marks, Peter; Rofail, Diana; Abetz, Linda; Baladi, Jean-Francois

2008-01-01

There is increasing evidence demonstrating the value of transfusions in sickle cell disease (SCD). However, resultant iron overload can be life threatening if untreated. Chelation therapy with deferoxamine requires parenteral infusions that can negatively impact quality of life and adherence to treatment. As part of a phase II trial, SCD patient-reported outcomes were evaluated. One hundred and ninety-five patients were randomized (2:1) to receive oral deferasirox (5-30 mg/kg/day) or deferoxamine (20-50 mg/kg, 5 days per week); 121 had previously received deferoxamine. At each time point, significantly more patients who had previously received deferoxamine were 'satisfied/very satisfied' with deferasirox, or found treatment to be 'convenient/very convenient' compared with deferoxamine (p < 0.001). In these patients, fewer hours were lost from daily activities with deferasirox than deferoxamine treatment. Most patients (77%) preferred deferasirox, and more were willing to continue taking deferasirox than deferoxamine at end-of-study (84 vs. 11%, respectively). Patients with SCD are therefore more satisfied with deferasirox, which has a lower impact on daily activities than deferoxamine. Given the high levels of satisfaction, it is likely that quality of life will be improved. These results also suggest that treatment adherence with deferasirox may be better than with deferoxamine, which should lead to improved long-term outcomes. 2008 S. Karger AG, Basel.

Publication rates of abstracts presented at the Association of Chiropractic Colleges Educational Conference/Research Agenda Conference from 2002 to 2008

PubMed Central

Bakkum, Barclay W.; Chapman, Cynthia; Johnson, Claire

2014-01-01

Objective The purposes of this study were to investigate the overall publication rates of presentations at the Association of Chiropractic Colleges Educational Conference/Research Agenda Conference (ACC/RAC) meetings (2002–2008), differences in the publication rates of platform vs poster presentations, and the consistency of the meeting abstract compared to the full-length journal article. Methods Abstracts were obtained from proceedings published in the Journal of Chiropractic Education. Literature searches using PubMed and the Index to the Chiropractic Literature (ICL) were performed to locate peer-reviewed journal articles based upon those abstracts. Whether the article was based upon a poster or platform presentation, and the congruence of the information in the abstract and article were recorded. Results We identified 776 proceeding abstracts, 249 of which eventually were published between 2002 and 2012. The overall publication rate was 32.2%. A total of 42.7% of platform presentations eventually were published vs 20.3% of posters. Congruency showed that 43.2% had the same title as the meeting abstract, 59.7% had the same authorship, and 88.8% had the same methods. Conclusion Publication rates of abstracts from spine and orthopedic surgery national meetings range from 34% to 59%. The ACC/RAC meetings have similar publication rates. More platform than poster presentations reach full publication. The congruency of ACC/RAC abstracts to published articles is higher than national meetings in other fields. PMID:24295363

Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics

PubMed Central

Hollmann, Markus W; Ritter, Carsten H; Henle, Philipp; de Klaver, Manuela; Kamatchi, Ganesan L; Durieux, Marcel E

2001-01-01

Muscarinic m1 receptors are inhibited by local anaesthetics (LA) at nM concentrations. To elucidate in more detail the site(s) of LA interaction, we compared these findings with LA effects on m3 muscarinic receptors. We expressed receptors in Xenopus oocytes. Using two-electrode voltage clamp, we measured the effects of lidocaine, QX314 (permanently charged) and benzocaine (permanently uncharged) on Ca2+-activated Cl−-currents (ICl(Ca)), elicited by acetyl-β-methylcholine bromide (MCh). We also characterized the interaction of lidocaine with [3H]-quinuclydinyl benzylate ([3H]-QNB) binding to m3 receptors. Antisense-injection was used to determine the role of specific G-protein α subunits in mediating the inhibitory effects of LA. Using chimeric receptor constructs we investigated which domains of the muscarinic receptors contribute to the binding site for LA. Lidocaine inhibited m3-signalling in a concentration-dependent, reversible, non-competitive manner with an IC50 of 370 nM, approximately 21 fold higher than the IC50 (18 nM) reported for m1 receptors. Intracellular inhibition of both signalling pathways by LA was similar, and dependent on the Gq- protein α subunit. In contrast to results reported for the m1 receptor, the m3 receptor lacks the major extracellular binding site for charged LA. The N-terminus and third extracellular loop of the m1 muscarinic receptor molecule were identified as requirements to obtain extracellular inhibition by charged LA. PMID:11325812

Detection of active noise control on the standard motorcycle exhaust Supra X 125 D using PVC pipe technique form Y

NASA Astrophysics Data System (ADS)

Isranuri, I.; Alfisyahrin; Nasution, A. R.

2018-02-01

This detection aims to obtain noise reduction on the supra X 125D motorcycle exhaust by using the Active Noise Control Method. The technique is done using a Y-shaped PVC pipe to be bolted on the exhaust, which then branch Y PVC is placed loudspeaker with impermeable conditions. The function of this loudspeaker is as a secondary noise to counter the primary noise of the sound of exhaust motorcycle Supra X 125D. The sound generator in this study is the ISD 4004 module, which serves to generate noise to counter the source noise. How this ISD 4004 module works is by recording source noise then recording the source noise and then reversed the phase 180° by phase reversing circuit. So that, the noise generated by the sound generator will hit the source noise and encounter or such as addition of two different phase of sound will result in noise reduction when detected at the end of the Y-shaped PVC pipe. Inverted phase reversed using feed-back resistor 1 kΩ and 2 kΩ input resistors, 16V capacitor 2500μf and as amplifier using ICL 7660 and TL 702 CP. Test results on the highest 1000 rpm rotation engine speed on the Z axis of 2 dB, and at the highest 2000 rpm rotation engine speed also occurs on the Z axis of 1.5 dB.

High brightness diode lasers controlled by volume Bragg gratings

NASA Astrophysics Data System (ADS)

Glebov, Leonid

2017-02-01

Volume Bragg gratings (VBGs) recorded in photo-thermo-refractive (PTR) glass are holographic optical elements that are effective spectral and angular filters withstanding high power laser radiation. Reflecting VBGs are narrow-band spectral filters while transmitting VBGs are narrow-band angular filters. The use of these optical elements in external resonators of semiconductor lasers enables extremely resonant feedback that provides dramatic spectral and angular narrowing of laser diodes radiation without significant power and efficiency penalty. Spectral narrowing of laser diodes by reflecting VBGs demonstrated in wide spectral region from near UV to 3 μm. Commercially available VBGs have spectral width ranged from few nanometers to few tens of picometers. Efficient spectral locking was demonstrated for edge emitters (single diodes, bars, modules, and stacks), vertical cavity surface emitting lasers (VCSELs), grating coupled surface emitting lasers (GCSELs), and interband cascade lasers (ICLs). The use of multiplexed VBGs provides multiwavelength emission from a single emitter. Spectrally locked semiconductor lasers demonstrated CW power from milliwatts to a kilowatt. Angular narrowing by transmitting VBGs enables single transverse mode emission from wide aperture diode lasers having resonators with great Fresnel numbers. This feature provides close to diffraction limit divergence along a slow axis of wide stripe edge emitters. Radiation exchange between lasers by means of spatially profiled or multiplexed VBGs enables coherent combining of diode lasers. Sequence of VBGs or multiplexed VBGs enable spectral combining of spectrally narrowed diode lasers or laser modules. Thus the use of VBGs for diode lasers beam control provides dramatic increase of brightness.

Space Transportation System Liftoff Debris Mitigation Process Overview

NASA Technical Reports Server (NTRS)

Mitchell, Michael; Riley, Christopher

2011-01-01

Liftoff debris is a top risk to the Space Shuttle Vehicle. To manage the Liftoff debris risk, the Space Shuttle Program created a team with in the Propulsion Systems Engineering & Integration Office. The Shutt le Liftoff Debris Team harnesses the Systems Engineering process to i dentify, assess, mitigate, and communicate the Liftoff debris risk. T he Liftoff Debris Team leverages off the technical knowledge and expe rtise of engineering groups across multiple NASA centers to integrate total system solutions. These solutions connect the hardware and ana lyses to identify and characterize debris sources and zones contribut ing to the Liftoff debris risk. The solutions incorporate analyses sp anning: the definition and modeling of natural and induced environmen ts; material characterizations; statistical trending analyses, imager y based trajectory analyses; debris transport analyses, and risk asse ssments. The verification and validation of these analyses are bound by conservative assumptions and anchored by testing and flight data. The Liftoff debris risk mitigation is managed through vigilant collab orative work between the Liftoff Debris Team and Launch Pad Operation s personnel and through the management of requirements, interfaces, r isk documentation, configurations, and technical data. Furthermore, o n day of launch, decision analysis is used to apply the wealth of ana lyses to case specific identified risks. This presentation describes how the Liftoff Debris Team applies Systems Engineering in their proce sses to mitigate risk and improve the safety of the Space Shuttle Veh icle.

Application of β-glucuronidase (GusA) as an effective reporter for extremely acidophilic Acidithiobacillus ferrooxidans.

PubMed

Wang, Huiyan; Fang, Liangyan; Wen, Qing; Lin, Jianqun; Liu, Xiangmei

2017-04-01

Acidithiobacillus ferrooxidans is a model organism for investigating metal sulfide bioleaching. The regulatory mechanism of gene expression by metabolizing various substrates is critical for understanding its role in bioleaching processes. However, no reporter has been successfully employed to study gene expression in A. ferrooxidans to date. In this study, a sensitive and robust reporter system based on β-glucuronidase (GusA) was described for feasible application in A. ferrooxidans. A set of vectors, which contained the transcriptional and translational fusions of gusA, were constructed and employed to analyze promoter activity and efficiency of translation initiation in A. ferrooxidans. Ptac and P2811 were screened out from ten tested promoters and could be used as strong promoters for gene overexpression in A. ferrooxidans. Among the four translational fusions of gusA with different start codons, ATG was most active, followed by TTG and GTG, while CTG showed the least activity. The transcriptional inhibition effect of an IclR-like transcription factor was also observed on its own encoding gene AFE_1668 as well as its neighboring AFE_1667. In addition, the specific chromogenic reaction of GusA could be detected and visualized by colonies of A. ferrooxidans containing gusA expression plasmids. Generally, the established GusA reporter system would be applied not only for quantitative analysis of promoter strength and its transcriptional regulation but also for qualitative colony screening in A. ferrooxidans in the future.

Cloning and expression of sheep renal K-CI cotransporter-1.

PubMed

Zhang, Jin J; Misri, Sandeep; Adragna, Norma C; Gagnon, Kenneth B E; Fyffe, Robert E W; Lauf, Peter K

2005-01-01

Sheep K-Cl cotransporter-1(shKCC1) cDNA was cloned from kidney by RT-PCR with an open reading frame of 3258 base pairs exhibiting 92%, 90%, 88% and 87% identity with pig, rabbit and human, rat and mouse KCC1 cDNAs, respectively, encoding an approximately 122 kDa polypeptide of 1086-amino acids. Hydropathy analysis reveals the familiar KCC1 topology with 12 transmembrane domains (TMDs) and the hydrophilic NH2-terminal (NTD) and COOH-terminal (CTD) domains both at the cytoplasmic membrane face. However, shKCC1 has two rather than one large extracellular loops (ECL): ECL3 between TMDs 5 and 6, and ECL6, between TMDs 11 and 12. The translated shKCC1 protein differs in 12 amino acid residues from other KCC1s, mainly within the NTD, ECL3, ICL4, ECL6, and CTD. Notably, a tyrosine residue at position 996 replaces aspartic acid conserved in all other species. Human embryonic kidney (HEK293) cells and mouse NIH/3T3 fibroblasts, transiently transfected with shKCCI-cDNA, revealed the glycosylated approximately 150 kDa proteins by Western blots and positive immunofluorescence-staining with polyclonal rabbit anti-ratKCC1 antibodies. ShKCC1 was functionally expressed in NIH/3T3 cells by an elevated basal Cl-dependent K influx measured with Rb as K-congener that was stimulated three-fold by the KCC-activator N-ethylmaleimide. Copyright (c) 2005 S. Karger AG, Basel.

Disparate requirements for the Walker A and B ATPase motifs of human RAD51D in homologous recombination.

PubMed

Wiese, Claudia; Hinz, John M; Tebbs, Robert S; Nham, Peter B; Urbin, Salustra S; Collins, David W; Thompson, Larry H; Schild, David

2006-01-01

In vertebrates, homologous recombinational repair (HRR) requires RAD51 and five RAD51 paralogs (XRCC2, XRCC3, RAD51B, RAD51C and RAD51D) that all contain conserved Walker A and B ATPase motifs. In human RAD51D we examined the requirement for these motifs in interactions with XRCC2 and RAD51C, and for survival of cells in response to DNA interstrand crosslinks (ICLs). Ectopic expression of wild-type human RAD51D or mutants having a non-functional A or B motif was used to test for complementation of a rad51d knockout hamster CHO cell line. Although A-motif mutants complement very efficiently, B-motif mutants do not. Consistent with these results, experiments using the yeast two- and three-hybrid systems show that the interactions between RAD51D and its XRCC2 and RAD51C partners also require a functional RAD51D B motif, but not motif A. Similarly, hamster Xrcc2 is unable to bind to the non-complementing human RAD51D B-motif mutants in co-immunoprecipitation assays. We conclude that a functional Walker B motif, but not A motif, is necessary for RAD51D's interactions with other paralogs and for efficient HRR. We present a model in which ATPase sites are formed in a bipartite manner between RAD51D and other RAD51 paralogs.

Characterization of metabolic network of oxalic acid biosynthesis through RNA seq data analysis of developing spikes of finger millet (Eleusine coracana): Deciphering the role of key genes involved in oxalate formation in relation to grain calcium accumulation.

PubMed

Akbar, Naved; Gupta, Supriya; Tiwari, Apoorv; Singh, K P; Kumar, Anil

2018-04-05

In the present study, we identified seven major genes of oxalic acid biosynthesis pathway (SGAT, GGAT, ICL, GLO, MHAR, APO and OXO) from developing spike transcriptome of finger millet using rice as a reference. Sequence alignment of identified genes showed high similarity with their respective homolog in rice except for OXO and GLO. Transcript abundance (FPKM) reflects the higher accumulation of identified genes in GP-1 (low calcium genotype) as compared to GP-45 (high calcium genotype) which was further confirmed by qRT-PCR analysis, indicating differential oxalate formation in both genotypes. Determination of oxalic acid and tartaric acid content in developing spikes explain that higher oxalic acid content in GP-1 however, tartaric acid content was more in GP-45. Higher calcium content in GP-45 and lower oxalate accumulation may be due to the diversion of more ascorbic acid into tartaric acid and may correspond to less formation of calcium oxalate. Our results suggest that more than one pathway for oxalic acid biosynthesis might be present in finger millet with probable predominance of ascorbate-tartarate pathway rather than glyoxalate-oxalate conversion. Thus, finger millet can be use as an excellent model system for understanding more specific role of nutrients-antinutrients interactions, as evident from the present study. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular characterization of Ambler class A to D β-lactamases, ISAba1, and integrons reveals multidrug-resistant Acinetobacter spp. isolates in northeastern China.

PubMed

Sun, Xiaoyu; Liu, Bin; Chen, Yan; Huang, Honglan; Wang, Guoqing; Li, Fan; Ni, Zhaohui

2016-12-01

The prevalence of various Ambler class A to D β-lactamases, ISAba1, and class 1 and 2 integrons as well as the clonal relatedness in 105 Acinetobacter spp. isolates found in northeastern China was investigated. All 105 Acinetobacter spp. isolates were determined to be multidrug resistant (MDR), and the resistance rates to carbapenem agents were approximately 50%. PER, IMP, AmpC, and OXA-23 were found to be dominant β-lactamases belonging to different classes, respectively. This is the first report of the coexistence of bla PER , bla IMP , bla AmpC , and bla OXA-23-like genes in Acinetobacter spp. isolates from northeastern China. ISAba1 was found upstream of the bla OXA-23-like gene in 87.8% (36/41) strains and upstream of the bla OXA-51-like gene in 26.5% (13/49) strains. ISAba3-like element was found upstream of the bla OXA-58-like gene in one bla OXA-58-like -positive strain. The presence of IntI1 was detected in 63.8% (67/105) of the isolates and the most prevalent gene cassettes were aacA4, aadA1, and catB8. The highly prevalent isolates belong to international clonal lineage (ICL)-II. These results indicate that the wide horizontal and clonal spread of MDR Acinetobacter spp. isolates harbouring multiple β-lactamase genes has become a serious problem in northeastern China.

The Aspergillus nidulans Pyruvate Dehydrogenase Kinases Are Essential To Integrate Carbon Source Metabolism.

PubMed

Ries, Laure Nicolas Annick; de Assis, Leandro José; Rodrigues, Fernando José Santos; Caldana, Camila; Rocha, Marina Campos; Malavazi, Iran; Bayram, Özgür; Goldman, Gustavo H

2018-05-24

The pyruvate dehydrogenase complex (PDH), that converts pyruvate to acetyl-coA, is regulated by pyruvate dehydrogenase kinases (PDHK) and phosphatases (PDHP) that have been shown to be important for morphology, pathogenicity and carbon source utilisation in different fungal species. The aim of this study was to investigate the role played by the three PDHKs PkpA, PkpB and PkpC in carbon source utilisation in the reference filamentous fungus Aspergillus nidulans , in order to unravel regulatory mechanisms which could prove useful for fungal biotechnological and biomedical applications. PkpA and PkpB were shown to be mitochondrial whereas PkpC localised to the mitochondria in a carbon source-dependent manner. Only PkpA was shown to regulate PDH activity. In the presence of glucose, deletion of pkpA and pkpC resulted in reduced glucose utilisation, which affected carbon catabolite repression (CCR) and hydrolytic enzyme secretion, due to de-regulated glycolysis and TCA cycle enzyme activities. Furthermore, PkpC was shown to be required for the correct metabolic utilisation of cellulose and acetate. PkpC negatively regulated the activity of the glyoxylate cycle enzyme isocitrate lyase (ICL), required for acetate metabolism. In summary, this study identified PDHKs important for the regulation of central carbon metabolism in the presence of different carbon sources, with effects on the secretion of biotechnologically important enzymes and carbon source-related growth. This work demonstrates how central carbon metabolism can affect a variety of fungal traits and lays a basis for further investigation into these characteristics with potential interest for different applications. Copyright © 2018, G3: Genes, Genomes, Genetics.

Origin of the Okrouhlá Radouň episyenite-hosted uranium deposit, Bohemian Massif, Czech Republic: fluid inclusion and stable isotope constraints

NASA Astrophysics Data System (ADS)

Dolníček, Zdeněk; René, Miloš; Hermannová, Sylvie; Prochaska, Walter

2014-04-01

The Okrouhlá Radouň shear zone hosted uranium deposit is developed along the contact of Variscan granites and high-grade metasedimentary rocks of the Moldanubian Zone of the Bohemian Massif. The pre-ore pervasive alteration of wall rocks is characterized by chloritization of mafic minerals, followed by albitization of feldspars and dissolution of quartz giving rise to episyenites. The subsequent fluid circulation led to precipitation of disseminated uraninite and coffinite, and later on, post-ore quartz and carbonate mineralization containing base metal sulfides. The fluid inclusion and stable isotope data suggest low homogenization temperatures (˜50-140 °C during pre-ore albitization and post-ore carbonatization, up to 230 °C during pre-ore chloritization), variable fluid salinities (0-25 wt.% NaCl eq.), low fluid δ18O values (-10 to +2 ‰ V-SMOW), low fluid δ13C values (-9 to -15 ‰ V-PDB), and highly variable ionic composition of the aqueous fluids (especially Na/Ca, Br/Cl, I/Cl, SO4/Cl, NO3/Cl ratios). The available data suggest participation of three fluid endmembers of primarily surficial origin during alteration and mineralization at the deposit: (1) local meteoric water, (2) Na-Ca-Cl basinal brines or shield brines, (3) SO4-NO3-Cl-(H)CO3 playa-like fluids. Pre-ore albitization was caused by circulation of alkaline, oxidized, and Na-rich playa fluids, whereas basinal/shield brines and meteoric water were more important during the post-ore stage of alteration.

Hydrogeochemical and isotopic evidences of groundwater salinization in coastal aquifers: A case study in Jeju volcanic island, Korea

NASA Astrophysics Data System (ADS)

Kim, Y.; Lee, D.; Lee, K.; Koh, D.; Lee, S.; Park, W.; Koh, G.; Woo, N.

2001-12-01

In order to clearly identify the origin of saline groundwaters in the eastern part of Jeju volcanic island, Korea the hydrogeochemical and isotopic studies have been carried out for 18 observation wells located in east and southeast coastal regions. The total dissolved solid (TDS) contents of groundwater samples are highly variable (77 to 21,782 mg/L). Most of the groundwaters in the study area are classified into Na-Cl type except a few samples showing Ca-Cl type. Hydrochemical characteristics based on bivariate and triangular diagrams of major ions show that the changes of chemical compositions of groundwaters were mainly controlled by the salinization process linked to cation-exchange reactions. The oxygen, hydrogen, sulfur, and strontium isotopic data explicitly show a simple mixing trend of groundwater and seawater. Using two-components fractional mixing model on the basis of 18O contents as well as Br and Cl contents, the proportion of seawater in fresh groundwater was quantitatively determined as high as 60 %. Sr isotopic compositions and Br/Cl ratios strongly suggest that the source of groundwater salinization is present-day seawater intrusion rather than paleoseawater or formation water, which can also be supported by the I/Cl ratios. The highly permeable aquifers in the east coastal region characterized by low hydraulic gradient and recharge rate and high hydraulic conductivity comparing with other regions are advantageous to the groundwater salinization. Based on the Cl, ¥ä18O, and 87Sr/86Sr it was determined that seawater has intruded into inland 2.5 km from coastline.

Widely applicable MATLAB routines for automated analysis of saccadic reaction times.

PubMed

Leppänen, Jukka M; Forssman, Linda; Kaatiala, Jussi; Yrttiaho, Santeri; Wass, Sam

2015-06-01

Saccadic reaction time (SRT) is a widely used dependent variable in eye-tracking studies of human cognition and its disorders. SRTs are also frequently measured in studies with special populations, such as infants and young children, who are limited in their ability to follow verbal instructions and remain in a stable position over time. In this article, we describe a library of MATLAB routines (Mathworks, Natick, MA) that are designed to (1) enable completely automated implementation of SRT analysis for multiple data sets and (2) cope with the unique challenges of analyzing SRTs from eye-tracking data collected from poorly cooperating participants. The library includes preprocessing and SRT analysis routines. The preprocessing routines (i.e., moving median filter and interpolation) are designed to remove technical artifacts and missing samples from raw eye-tracking data. The SRTs are detected by a simple algorithm that identifies the last point of gaze in the area of interest, but, critically, the extracted SRTs are further subjected to a number of postanalysis verification checks to exclude values contaminated by artifacts. Example analyses of data from 5- to 11-month-old infants demonstrated that SRTs extracted with the proposed routines were in high agreement with SRTs obtained manually from video records, robust against potential sources of artifact, and exhibited moderate to high test-retest stability. We propose that the present library has wide utility in standardizing and automating SRT-based cognitive testing in various populations. The MATLAB routines are open source and can be downloaded from http://www.uta.fi/med/icl/methods.html .

Directed evolution of P-glycoprotein cysteines reveals site-specific, non-conservative substitutions that preserve multidrug resistance.

PubMed

Swartz, Douglas J; Mok, Leo; Botta, Sri K; Singh, Anukriti; Altenberg, Guillermo A; Urbatsch, Ina L

2014-06-25

Pgp (P-glycoprotein) is a prototype ABC (ATP-binding-cassette) transporter involved in multidrug resistance of cancer. We used directed evolution to replace six cytoplasmic Cys (cysteine) residues in Pgp with all 20 standard amino acids and selected for active mutants. From a pool of 75000 transformants for each block of three Cys, we identified multiple mutants that preserved drug resistance and yeast mating activity. The most frequent substitutions were glycine and serine for Cys427 (24 and 20%, respectively) and Cys1070 (37 and 25%) of the Walker A motifs in the NBDs (nucleotide-binding domains), Cys1223 in NBD2 (25 and 8%) and Cys638 in the linker region (24 and 16%), whereas close-by Cys669 tolerated glycine (16%) and alanine (14%), but not serine (absent). Cys1121 in NBD2 showed a clear preference for positively charged arginine (38%) suggesting a salt bridge with Glu269 in the ICL2 (intracellular loop 2) may stabilize domain interactions. In contrast, three Cys residues in transmembrane α-helices could be successfully replaced by alanine. The resulting CL (Cys-less) Pgp was fully active in yeast cells, and purified proteins displayed drug-stimulated ATPase activities indistinguishable from WT (wild-type) Pgp. Overall, directed evolution identified site-specific, non-conservative Cys substitutions that allowed building of a robust CL Pgp, an invaluable new tool for future functional and structural studies, and that may guide the construction of other CL proteins where alanine and serine have proven unsuccessful.

ExtraTrain: a database of Extragenic regions and Transcriptional information in prokaryotic organisms

PubMed Central

Pareja, Eduardo; Pareja-Tobes, Pablo; Manrique, Marina; Pareja-Tobes, Eduardo; Bonal, Javier; Tobes, Raquel

2006-01-01

Background Transcriptional regulation processes are the principal mechanisms of adaptation in prokaryotes. In these processes, the regulatory proteins and the regulatory DNA signals located in extragenic regions are the key elements involved. As all extragenic spaces are putative regulatory regions, ExtraTrain covers all extragenic regions of available genomes and regulatory proteins from bacteria and archaea included in the UniProt database. Description ExtraTrain provides integrated and easily manageable information for 679816 extragenic regions and for the genes delimiting each of them. In addition ExtraTrain supplies a tool to explore extragenic regions, named Palinsight, oriented to detect and search palindromic patterns. This interactive visual tool is totally integrated in the database, allowing the search for regulatory signals in user defined sets of extragenic regions. The 26046 regulatory proteins included in ExtraTrain belong to the families AraC/XylS, ArsR, AsnC, Cold shock domain, CRP-FNR, DeoR, GntR, IclR, LacI, LuxR, LysR, MarR, MerR, NtrC/Fis, OmpR and TetR. The database follows the InterPro criteria to define these families. The information about regulators includes manually curated sets of references specifically associated to regulator entries. In order to achieve a sustainable and maintainable knowledge database ExtraTrain is a platform open to the contribution of knowledge by the scientific community providing a system for the incorporation of textual knowledge. Conclusion ExtraTrain is a new database for exploring Extragenic regions and Transcriptional information in bacteria and archaea. ExtraTrain database is available at . PMID:16539733

Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study

PubMed Central

Porter, John; Galanello, Renzo; Saglio, Giuseppe; Neufeld, Ellis J; Vichinsky, Elliott; Cappellini, Maria Domenica; Olivieri, Nancy; Piga, Antonio; Cunningham, Melody J; Soulières, Denis; Gattermann, Norbert; Tchernia, Gilbert; Maertens, Johan; Giardina, Patricia; Kwiatkowski, Janet; Quarta, Giovanni; Jeng, Michael; Forni, Gian Luca; Stadler, Michael; Cario, Holger; Debusscher, Louisette; Porta, Matteo Della; Cazzola, Mario; Greenberg, Peter; Alimena, Giuliana; Rabault, Bertrand; Gathmann, Insa; Ford, John Malcolm; Alberti, Daniele; Rose, Christian

2008-01-01

Objectives/methods This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3–81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond–Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or β-thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC). Results In patients with baseline LIC ≥7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC (P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 ± 0.14 mg/kg/d; greatest in DBA: 0.4 ± 0.11 mg/kg/d). Overall, LIC changes were dependent on dose (P < 0.001) and transfusional iron intake (P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group (r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases. Conclusions Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups. PMID:18028431

Factors contributing to hearing impairment in patients with cleft lip/palate in Malaysia: A prospective study of 346 ears.

PubMed

Cheong, Jack Pein; Soo, Siew Shuin; Manuel, Anura Michelle

2016-09-01

To determine the factors contributing towards hearing impairment in patients with cleft lip/palate. A prospective analysis was conducted on 173 patients (346 ears) with cleft lip and palate (CL/P) who presented to the combined cleft clinic at University Malaya Medical Centre (UMMC) over 12 months. The patients' hearing status was determined using otoacoustic emission (OAE), pure tone audiometry (PTA) and auditory brainstem response (ABR). These results were analysed against several parameters, which included age, gender, race, types of cleft pathology, impact and timing of repair surgery. The patients' age ranged from 1-26 years old. They comprised 30% with unilateral cleft lip and palate (UCLP), 28% with bilateral cleft lip and palate (BCLP), 28% with isolated cleft palate (ICP) and 14% with isolated cleft lip (ICL). Majority of the patients (68.2%) had normal otoscopic findings. Out of the 346 ears, 241 ears (70%) ears had passed the hearing tests. There was no significant relationship between patients' gender and ethnicity with their hearing status. The types of cleft pathology significantly influenced the outcome of PTA and ABR screening results (p < 0.001). There was no significant difference between the repaired and unrepaired cleft groups and the outcome of hearing tests. However, hearing improvement occurred when palatal repair was performed at the age of <1year old (OR = 2.37, CI 1.2 = 4.6, p = 0.01). Majority of the cleft patients had normal hearing (70%). Hearing threshold varied significantly between the different types of cleft pathology. Surgery conferred no significant impact on the hearing outcome unless surgery was performed at the age of <1 year old. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The clinical utility of cervical range of motion in diagnosis, prognosis, and evaluating the effects of manipulation: a systematic review.

PubMed

Snodgrass, Suzanne J; Cleland, Joshua A; Haskins, Robin; Rivett, Darren A

2014-12-01

Clinicians commonly assess cervical range of motion (ROM), but it has rarely been critically evaluated for its ability to contribute to patient diagnosis or prognosis, or whether it is affected by mobilisation/manipulation. This review summarises the methods used to measure cervical ROM in research involving patients with cervical spine disorders, reviews the evidence for using cervical ROM in patient diagnosis, prognosis, and evaluation of the effects of mobilisation/manipulation on cervical ROM. A systematic search of MEDLINE, EMBASE, CINAHL, AMED and ICL databases was conducted, addressing one of four constructs related to cervical ROM: measurement, diagnosis, prognosis, and the effects of mobilisation/manipulation on cervical ROM. Two independent raters appraised methodological quality using the QUADAS-2 tool for diagnostic studies, the QUIPS tool for prognostic studies and the PEDro scale for interventional studies. Heterogeneity of studies prevented meta-analysis. Thirty-six studies met the criteria and findings showed there is limited evidence for the diagnostic value of cervical ROM in cervicogenic headache, cervical radiculopathy and cervical spine injury. There is conflicting evidence for the prognostic value of cervical ROM, though restricted ROM appears associated with negative outcomes while greater ROM is associated with positive outcomes. There is conflicting evidence as to whether cervical ROM increases or decreases following mobilisation/manipulation. Cervical ROM has value as one component of assessment, but clinicians should be cautious about making clinical judgments primarily on the basis of cervical ROM. This collaboration was supported by an internal grant from the Faculty of Health, The University of Newcastle. Copyright © 2014 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

[A review of mixed gas detection system based on infrared spectroscopic technique].

PubMed

Dang, Jing-Min; Fu, Li; Yan, Zi-Hui; Zheng, Chuan-Tao; Chang, Yu-Chun; Chen, Chen; Wang, Yi-Din

2014-10-01

In order to provide the experiences and references to the researchers who are working on infrared (IR) mixed gas detection field. The proposed manuscript reviews two sections of the aforementioned field, including optical multiplexing structure and detection method. At present, the coherent light sources whose representative are quantum cascade laser (QCL) and inter-band cascade laser(ICL) become the mainstream light source in IR mixed gas detection, which replace the traditional non-coherent light source, such as IR radiation source and IR light emitting diode. In addition, the photon detector which has a super high detectivity and very short response time is gradually beyond thermal infrared detector, dominant in the field of infrared detector. The optical multiplexing structure is the key factor of IR mixed gas detection system, which consists of single light source multi-plexing detection structure and multi light source multiplexing detection structure. Particularly, single light source multiplexing detection structure is advantages of small volume and high integration, which make it a plausible candidate for the portable mixed gas detection system; Meanwhile, multi light source multiplexing detection structure is embodiment of time division multiplex, frequency division multiplexing and wavelength division multiplexing, and become the leading structure of the mixed gas detection system because of its wider spectral range, higher spectral resolution, etc. The detection method applied to IR mixed gas detection includes non-dispersive infrared (NDIR) spectroscopy, wavelength and frequency-modulation spectroscopy, cavity-enhanced spectroscopy and photoacoustic spectroscopy, etc. The IR mixed gas detection system designed by researchers after recognizing the whole sections of the proposed system, which play a significant role in industrial and agricultural production, environmental monitoring, and life science, etc.

The rhizoplast of chrysomonads, a basal body-nucleus connector that polarises the dividing spindle.

PubMed

Brugerolle, G; Mignot, J-P

2003-09-01

An ultrastructure study of the rhizoplast in Synura petersenii, Mallomonas fastigiata, and M. insignis shows that it consists of 15-20 striated rootlets that form a claw or an incomplete cone over the nucleus. These rootlets course along one face of the nucleus between the nuclear membrane and the cis-face of the Golgi stack of cisternae. They converge and merge above the nucleus, forming a stub attached to the proximal section of the two basal bodies. These cross-striated rootlets are composed of closely packed longitudinal microfibrils. By immunofluorescence, the basal bodies and the rootlets forming the claw were decorated by the anti-centrin monoclonal antibody ICL19 raised against the Paramecium tetraurelia acidic centrin protein and by two antibodies raised against the striated parabasal and costal striated fibres of trichomonads. Only the anti-centrin monoclonal antibody 20H5 raised against Chlamydomonas reinhardtii centrin strongly labelled the 20-22 kDa protein bands from the extracted cytoskeleton of S. petersenii by immunoblotting. Electron micrographs of mitosis in S. petersenii cells revealed that the segregated pairs of basal bodies are linked by the striated rootlets of the rhizoplast to the poles of the mitotic spindle. The spindle microtubules arise perpendicularly from the striated rootlets of the basal body-nucleus connector forming the centrosome. In conclusion, in these cells there is a basal body-nucleus connector similar to that of C. reinhardtii and other chlorophytes. It contains centrin proteins, it is involved in the linkage of the basal bodies to the nucleus and is a component of the spindle pole body or centrosome in the dividing cell.

Correlation between radio-induced lymphocyte apoptosis measurements obtained from two French centres.

PubMed

Mirjolet, C; Merlin, J L; Dalban, C; Maingon, P; Azria, D

2016-07-01

In the era of modern treatment delivery, increasing the dose delivered to the target to improve local control might be modulated by the patient's intrinsic radio-sensitivity. A predictive assay based on radio-induced lymphocyte apoptosis quantification highlighted the significant correlation between CD4 and CD8 T-lymphocyte apoptosis and grade 2 or 3 radiation-induced late toxicities. By conducting this assay at several technical platforms, the aim of this study was to demonstrate that radio-induced lymphocyte apoptosis values obtained from two different platforms were comparable. For 25 patients included in the PARATOXOR trial running in Dijon the radio-induced lymphocyte apoptosis results obtained from the laboratory of Montpellier (IRCM, Inserm U1194, France), considered as the reference (referred to as Lab 1), were compared with those from the laboratory located at the Institut de cancérologie de Lorraine (ICL, France), referred to as Lab 2. Different statistical methods were used to measure the agreement between the radio-induced lymphocyte apoptosis data from the two laboratories (quantitative data). The Bland-Altman plot was used to identify potential bias. All statistical tests demonstrated good agreement between radio-induced lymphocyte apoptosis values obtained from both sites and no major bias was identified. Since radio-induced lymphocyte apoptosis values, which predict tolerance to radiotherapy, could be assessed by two laboratories and showed a high level of robustness and consistency, we can suggest that this assay be extended to any laboratories that use the same technique. Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

Multilocus Sequence Typing Reveals a New Cluster of Closely Related Candida tropicalis Genotypes in Italian Patients With Neurological Disorders.

PubMed

Scordino, Fabio; Giuffrè, Letterio; Barberi, Giuseppina; Marino Merlo, Francesca; Orlando, Maria Grazia; Giosa, Domenico; Romeo, Orazio

2018-01-01

Candida tropicalis is a pathogenic yeast that has emerged as an important cause of candidemia especially in elderly patients with hematological malignancies. Infections caused by this species are mainly reported from Latin America and Asian-Pacific countries although recent epidemiological data revealed that C. tropicalis accounts for 6-16.4% of the Candida bloodstream infections (BSIs) in Italy by representing a relevant issue especially for patients receiving long-term hospital care. The aim of this study was to describe the genetic diversity of C. tropicalis isolates contaminating the hands of healthcare workers (HCWs) and hospital environments and/or associated with BSIs occurring in patients with different neurological disorders and without hematological disease. A total of 28 C. tropicalis isolates were genotyped using multilocus sequence typing analysis of six housekeeping ( ICL1, MDR1, SAPT2, SAPT4, XYR1 , and ZWF1 ) genes and data revealed the presence of only eight diploid sequence types (DSTs) of which 6 (75%) were completely new. Four eBURST clonal complexes (CC2, CC10, CC11, and CC33) contained all DSTs found in this study and the CC33 resulted in an exclusive, well-defined, clonal cluster from Italy. In conclusion, C. tropicalis could represent an important cause of BSIs in long-term hospitalized patients with no underlying hematological disease. The findings of this study also suggest a potential horizontal transmission of a specific C. tropicalis clone through hands of HCWs and expand our understanding of the molecular epidemiology of this pathogen whose population structure is still far from being fully elucidated as its complexity increases as different categories of patients and geographic areas are examined.

The Homogentisate Pathway: a Central Catabolic Pathway Involved in the Degradation of l-Phenylalanine, l-Tyrosine, and 3-Hydroxyphenylacetate in Pseudomonas putida

PubMed Central

Arias-Barrau, Elsa; Olivera, Elías R.; Luengo, José M.; Fernández, Cristina; Galán, Beatriz; García, José L.; Díaz, Eduardo; Miñambres, Baltasar

2004-01-01

Pseudomonas putida metabolizes Phe and Tyr through a peripheral pathway involving hydroxylation of Phe to Tyr (PhhAB), conversion of Tyr into 4-hydroxyphenylpyruvate (TyrB), and formation of homogentisate (Hpd) as the central intermediate. Homogentisate is then catabolized by a central catabolic pathway that involves three enzymes, homogentisate dioxygenase (HmgA), fumarylacetoacetate hydrolase (HmgB), and maleylacetoacetate isomerase (HmgC), finally yielding fumarate and acetoacetate. Whereas the phh, tyr, and hpd genes are not linked in the P. putida genome, the hmgABC genes appear to form a single transcriptional unit. Gel retardation assays and lacZ translational fusion experiments have shown that hmgR encodes a specific repressor that controls the inducible expression of the divergently transcribed hmgABC catabolic genes, and homogentisate is the inducer molecule. Footprinting analysis revealed that HmgR protects a region in the Phmg promoter that spans a 17-bp palindromic motif and an external direct repetition from position −16 to position 29 with respect to the transcription start site. The HmgR protein is thus the first IclR-type regulator that acts as a repressor of an aromatic catabolic pathway. We engineered a broad-host-range mobilizable catabolic cassette harboring the hmgABC, hpd, and tyrB genes that allows heterologous bacteria to use Tyr as a unique carbon and energy source. Remarkably, we show here that the catabolism of 3-hydroxyphenylacetate in P. putida U funnels also into the homogentisate central pathway, revealing that the hmg cluster is a key catabolic trait for biodegradation of a small number of aromatic compounds. PMID:15262943

The homogentisate pathway: a central catabolic pathway involved in the degradation of L-phenylalanine, L-tyrosine, and 3-hydroxyphenylacetate in Pseudomonas putida.

PubMed

Arias-Barrau, Elsa; Olivera, Elías R; Luengo, José M; Fernández, Cristina; Galán, Beatriz; García, José L; Díaz, Eduardo; Miñambres, Baltasar

2004-08-01

Pseudomonas putida metabolizes Phe and Tyr through a peripheral pathway involving hydroxylation of Phe to Tyr (PhhAB), conversion of Tyr into 4-hydroxyphenylpyruvate (TyrB), and formation of homogentisate (Hpd) as the central intermediate. Homogentisate is then catabolized by a central catabolic pathway that involves three enzymes, homogentisate dioxygenase (HmgA), fumarylacetoacetate hydrolase (HmgB), and maleylacetoacetate isomerase (HmgC), finally yielding fumarate and acetoacetate. Whereas the phh, tyr, and hpd genes are not linked in the P. putida genome, the hmgABC genes appear to form a single transcriptional unit. Gel retardation assays and lacZ translational fusion experiments have shown that hmgR encodes a specific repressor that controls the inducible expression of the divergently transcribed hmgABC catabolic genes, and homogentisate is the inducer molecule. Footprinting analysis revealed that HmgR protects a region in the Phmg promoter that spans a 17-bp palindromic motif and an external direct repetition from position -16 to position 29 with respect to the transcription start site. The HmgR protein is thus the first IclR-type regulator that acts as a repressor of an aromatic catabolic pathway. We engineered a broad-host-range mobilizable catabolic cassette harboring the hmgABC, hpd, and tyrB genes that allows heterologous bacteria to use Tyr as a unique carbon and energy source. Remarkably, we show here that the catabolism of 3-hydroxyphenylacetate in P. putida U funnels also into the homogentisate central pathway, revealing that the hmg cluster is a key catabolic trait for biodegradation of a small number of aromatic compounds.

Characterization of a Gene Cluster Involved in 4-Chlorocatechol Degradation by Pseudomonas reinekei MT1▿

PubMed Central

Cámara, Beatriz; Nikodem, Patricia; Bielecki, Piotr; Bobadilla, Roberto; Junca, Howard; Pieper, Dietmar H.

2009-01-01

Pseudomonas reinekei MT1 has previously been reported to degrade 4- and 5-chlorosalicylate by a pathway with 4-chlorocatechol, 3-chloromuconate, 4-chloromuconolactone, and maleylacetate as intermediates, and a gene cluster channeling various salicylates into an intradiol cleavage route has been reported. We now report that during growth on 5-chlorosalicylate, besides a novel (chloro)catechol 1,2-dioxygenase, C12OccaA, a novel (chloro)muconate cycloisomerase, MCIccaB, which showed features not yet reported, was induced. This cycloisomerase, which was practically inactive with muconate, evolved for the turnover of 3-substituted muconates and transforms 3-chloromuconate into equal amounts of cis-dienelactone and protoanemonin, suggesting that it is a functional intermediate between chloromuconate cycloisomerases and muconate cycloisomerases. The corresponding genes, ccaA (C12OccaA) and ccaB (MCIccaB), were located in a 5.1-kb genomic region clustered with genes encoding trans-dienelactone hydrolase (ccaC) and maleylacetate reductase (ccaD) and a putative regulatory gene, ccaR, homologous to regulators of the IclR-type family. Thus, this region includes genes sufficient to enable MT1 to transform 4-chlorocatechol to 3-oxoadipate. Phylogenetic analysis showed that C12OccaA and MCIccaB are only distantly related to previously described catechol 1,2-dioxygenases and muconate cycloisomerases. Kinetic analysis indicated that MCIccaB and the previously identified C12OsalD, rather than C12OccaA, are crucial for 5-chlorosalicylate degradation. Thus, MT1 uses enzymes encoded by a completely novel gene cluster for degradation of chlorosalicylates, which, together with a gene cluster encoding enzymes for channeling salicylates into the ortho-cleavage pathway, form an effective pathway for 4- and 5-chlorosalicylate mineralization. PMID:19465655

Benzoate Metabolism Intermediate Benzoyl Coenzyme A Affects Gentisate Pathway Regulation in Comamonas testosteroni

PubMed Central

Chen, Dong-Wei; Zhang, Yun; Jiang, Cheng-Ying

2014-01-01

A previous study showed that benzoate was catabolized via a coenzyme A (CoA)-dependent epoxide pathway in Azoarcus evansii (R. Niemetz, U. Altenschmidt, S. Brucker, and G. Fuchs, Eur. J. Biochem. 227:161-168, 1995), but gentisate 1,2-dioxygenase was induced. Similarly, we found that the Comamonas testosteroni strain CNB-1 degraded benzoate via a CoA-dependent epoxide pathway and that gentisate 1,2-dioxygenase (GenA) was also induced when benzoate or 3-hydroxybenzoate served as a carbon source for growth. Genes encoding the CoA-dependent epoxide (box genes) and gentisate (gen genes) pathways were identified. Genetic disruption revealed that the gen genes were not involved in benzoate and 3-hydroxybenzoate degradation. Hence, we investigated gen gene regulation in the CNB-1 strain. The PgenA promoter, a MarR-type regulator (GenR), and the GenR binding site were identified. We found that GenR took gentisate, 3-hydroxybenzoate, and benzoyl-CoA as effectors and that binding of GenR to its target DNA sequence was prohibited when these effectors were present. In vivo studies showed that the CNB-1 mutant that lost benzoyl-CoA synthesis was not able to activate PgenA promoter, while transcription of genA was upregulated in another CNB-1 mutant that lost the ability to degrade benzoyl-CoA. The finding that benzoyl-CoA (a metabolic intermediate of benzoate degradation) and 3-hydroxybenzoate function as GenR effectors explains why GenA was induced when CNB-1 grew on benzoate or 3-hydroxybenzoate. Regulation of gentisate pathways by MarR-, LysR-, and IclR-type regulators in diverse bacterial groups is discussed in detail. PMID:24771026

Differential impact of ionic and coordinate covalent chromium (Cr)-DNA binding on DNA replication.

PubMed

Fornsaglio, Jamie L; O'Brien, Travis J; Patierno, Steven R

2005-11-01

The reactive species produced by the reduction of Cr(VI), particularly Cr(III), can form both ionic and coordinate covalent complexes with DNA. These Cr(III)-DNA interactions consist of Cr-DNA monoadducts, Cr-DNA ternary adducts, and Cr-DNA interstrand cross-links (Cr-ICLs), the latter of which are DNA polymerase arresting lesions (PALs). We sought to determine the impact of Cr-DNA interactions on the formation of replication blocking lesions in S. cerevisiae using a PCR-based method. We found that target sequence (TS) amplification using DNA isolated from Cr(VI)-treated yeast actually increased as a function of Cr(VI) concentration. Moreover, the enhanced TS amplification was reproduced in vitro using Cr(III)-treated DNA. In contrast, PCR amplification of TS from DNA isolated from yeast exposed to equitoxic doses of the inorganic DNA cross-linking agent cisplatin (CDDP), was decreased in a concentration-dependent manner. This paradox suggested that a specific Cr-DNA interaction, such as an ionic Cr-DNA complex, was responsible for the enhanced TS amplification, thereby masking the replication-blocking effect of certain ternary Cr-DNA adducts (i.e. interstrand cross-links). To test this possibility, we removed ionically associated Cr from the DNA using salt extraction prior to PCR analysis. This procedure obviated the increased amplification and revealed a dose-dependent decrease in TS amplification and an increase in Cr-PALs. These data from DNA analyzed ex vivo after treatment of intact cells indicate that ionic interactions of Cr with DNA result in increased DNA amplification whereas coordinate-covalent Cr-DNA complexes lead to formation of Cr-PALs. Thus, these results suggest that treatment of living cells with Cr(VI) leads to two modes of Cr-binding, which may have conflicting effects on DNA replication.

Weak endogenous Ca2+ buffering supports sustained synaptic transmission by distinct mechanisms in rod and cone photoreceptors in salamander retina

PubMed Central

Van Hook, Matthew J; Thoreson, Wallace B

2015-01-01

Differences in synaptic transmission between rod and cone photoreceptors contribute to different response kinetics in rod- versus cone-dominated visual pathways. We examined Ca2+ dynamics in synaptic terminals of tiger salamander photoreceptors under conditions that mimicked endogenous buffering to determine the influence on kinetically and mechanistically distinct components of synaptic transmission. Measurements of ICl(Ca) confirmed that endogenous Ca2+ buffering is equivalent to ˜0.05 mmol/L EGTA in rod and cone terminals. Confocal imaging showed that with such buffering, depolarization stimulated large, spatially unconstrained [Ca2+] increases that spread throughout photoreceptor terminals. We calculated immediately releasable pool (IRP) size and release efficiency in rods by deconvolving excitatory postsynaptic currents and presynaptic Ca2+ currents. Peak efficiency of ˜0.2 vesicles/channel was similar to that of cones (˜0.3 vesicles/channel). Efficiency in both cell types was not significantly affected by using weak endogenous Ca2+ buffering. However, weak Ca2+ buffering speeded Ca2+/calmodulin (CaM)-dependent replenishment of vesicles to ribbons in both rods and cones, thereby enhancing sustained release. In rods, weak Ca2+ buffering also amplified sustained release by enhancing CICR and CICR-stimulated release of vesicles at nonribbon sites. By contrast, elevating [Ca2+] at nonribbon sites in cones with weak Ca2+ buffering and by inhibiting Ca2+ extrusion did not trigger additional release, consistent with the notion that exocytosis from cones occurs exclusively at ribbons. The presence of weak endogenous Ca2+ buffering in rods and cones facilitates slow, sustained exocytosis by enhancing Ca2+/CaM-dependent replenishment of ribbons in both rods and cones and by stimulating nonribbon release triggered by CICR in rods. PMID:26416977

Inhibition of Krebs cycle and activation of glyoxylate cycle in the course of chronological aging of Saccharomyces cerevisiae. Compensatory role of succinate oxidation.

PubMed

Samokhvalov, V; Ignatov, V; Kondrashova, M

2004-01-01

We investigated oxidative processes in mitochondria of Saccharomyces cerevisiae grown on ethanol in the course of chronological aging. We elaborated a model of chronological aging that avoids the influence of exhaustion of medium, as well as the accumulation of toxic metabolites during aging. A decrease in total respiration of cells and, even more, of the contribution of respiration coupled with ATP-synthesis was observed during aging. Aging is also related with the decrease of the contribution of malonate-insensitive respiration. Activities of citrate-synthase (CS), alpha-ketoglutarate dehydrogenase (KGDH) and malate dehydrogenase (MDH) were threefold decreased. The activity of NADP-dependent isocitrate dehydrogenase (NADP-ICDH) decreased more significantly, while the activity of NAD-dependent isocitrate dehydrogenase (NAD-ICDH) fell even greater, being completely inactivated on the third week of aging. In contrast, succinate dehydrogenase (SDH), enzymes of glyoxylate cycle (GCL) (isocitrate lyase (ICL) and malate synthase (MLS)), and enzymes of ethanol oxidation (alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ACDH)), were activated by 50% or more. The behavior of oxidative enzymes and metabolic pathways are apparently inherent to a more viable, long-lived cells in population, selected in the course of chronological aging. This selection allows cells to reveal the mechanism of their higher viability as caused by shunting of complete Krebs cycle by glyoxylate cycle, with a concomitant increased rate of the most efficient energy source, namely succinate formation and oxidation. Thiobarbituric-reactive species (TAR species) increased during aging. We supposed that to be the immediate cause of damage of a part of yeast population. These data show that a greater succinate contribution to respiration in more active cells is a general property of yeast and animal tissues.

Contribution of the tricarboxylic acid (TCA) cycle and the glyoxylate shunt in Saccharomyces cerevisiae to succinic acid production during dough fermentation.

PubMed

Rezaei, Mohammad N; Aslankoohi, Elham; Verstrepen, Kevin J; Courtin, Christophe M

2015-07-02

Succinic acid produced by yeast during bread dough fermentation can significantly affect the rheological properties of the dough. By introducing mutations in the model S288C yeast strain, we show that the oxidative pathway of the TCA cycle and the glyoxylate shunt contribute significantly to succinic acid production during dough fermentation. More specifically, deletion of ACO1 and double deletion of ACO1 and ICL1 resulted in a 36 and 77% decrease in succinic acid levels in fermented dough, respectively. Similarly, double deletion of IDH1 and IDP1 decreased succinic acid production by 85%, while also affecting the fermentation rate. By contrast, double deletion of SDH1 and SDH2 resulted in a two-fold higher succinic acid accumulation compared to the wild-type. Deletion of fumarate reductase activity (FRD1 and OSM1) in the reductive pathway of the TCA cycle did not affect the fermentation rate and succinic acid production. The changes in the levels of succinic acid produced by mutants Δidh1Δidp1 (low level) and Δsdh1Δsdh2 (high level) in fermented dough only resulted in small pH differences, reflecting the buffering capacity of dough at a pH of around 5.1. Moreover, Rheofermentometer analysis using these mutants revealed no difference in maximum dough height and gas retention capacity with the dough prepared with S288C. The impact of the changed succinic acid profile on the organoleptic or antimicrobial properties of bread remains to be demonstrated. Copyright © 2015 Elsevier B.V. All rights reserved.

Noble gases fingerprint a metasedimentary fluid source in the Macraes orogenic gold deposit, New Zealand

NASA Astrophysics Data System (ADS)

Goodwin, Nicholas R. J.; Burgess, Ray; Craw, Dave; Teagle, Damon A. H.; Ballentine, Chris J.

2017-02-01

The world-class Macraes orogenic gold deposit (˜10 Moz resource) formed during the late metamorphic uplift of a metasedimentary schist belt in southern New Zealand. Mineralising fluids, metals and metalloids were derived from within the metasedimentary host. Helium and argon extracted from fluid inclusions in sulphide mineral grains (three crush extractions from one sample) have crustal signatures, with no evidence for mantle input (R/Ra = 0.03). Xenon extracted from mineralised quartz samples provides evidence for extensive interaction between fluid and maturing organic material within the metasedimentary host rocks, with 132Xe/36Ar ratios up to 200 times greater than air. Similarly, I/Cl ratios for fluids extracted from mineralised quartz are similar to those of brines from marine sediments that have interacted with organic matter and are ten times higher than typical magmatic/mantle fluids. The Macraes mineralising fluids were compositionally variable, reflecting either mixing of two different crustal fluids in the metasedimentary pile or a single fluid type that has had varying degrees of interaction with the host metasediments. Evidence for additional input of meteoric water is equivocal, but minor meteoric incursion cannot be discounted. The Macraes deposit formed in a metasedimentary belt without associated coeval magmatism, and therefore represents a purely crustal metamorphogenic end member in a spectrum of orogenic hydrothermal processes that can include magmatic and/or mantle fluid input elsewhere in the world. There is no evidence for involvement of minor intercalated metabasic rocks in the Macraes mineralising system. Hydrothermal fluids that formed other, smaller, orogenic deposits in the same metamorphic belt have less pronounced noble gas and halogen evidence for crustal fluid-rock interaction than at Macraes, but these deposits also formed from broadly similar metamorphogenic processes.

A structured review of spinal stiffness as a kinesiological outcome of manipulation: its measurement and utility in diagnosis, prognosis and treatment decision-making.

PubMed

Snodgrass, Suzanne J; Haskins, Robin; Rivett, Darren A

2012-10-01

To review and discuss the methods used for measuring spinal stiffness and factors associated with stiffness, how stiffness is used in diagnosis, prognosis, and treatment decision-making and the effects of manipulative techniques on stiffness. A systematic search of MEDLINE, EMBASE, CINAHL, AMED and ICL databases was conducted. Included studies addressed one of four constructs related to stiffness: measurement, diagnosis, prognosis and/or treatment decision-making, and the effects of manipulation on stiffness. Spinal stiffness was defined as the relationship between force and displacement. One hundred and four studies are discussed in this review, with the majority of studies focused on the measurement of stiffness, most often in asymptomatic persons. Eight studies investigated spinal stiffness in diagnosis, providing limited evidence that practitioner-judged stiffness is associated with radiographic findings of sagittal rotational mobility. Fifteen studies investigated spinal stiffness in prognosis or treatment decision-making, providing limited evidence that spinal stiffness is unlikely to independently predict patient outcomes, though stiffness may influence a practitioner's application of non-thrust manipulative techniques. Nine studies investigating the effects of manipulative techniques on spinal stiffness provide very limited evidence that there is no change in spinal stiffness following thrust or non-thrust manipulation in asymptomatic individuals and non-thrust techniques in symptomatic persons, with only one study supporting an immediate, but not sustained, stiffness decrease following thrust manipulation in symptomatic individuals. The existing limited evidence does not support an association between spinal stiffness and manipulative treatment outcomes. There is a need for additional research investigating the effects of manipulation on spinal stiffness in persons with spinal pain. Copyright © 2012 Elsevier Ltd. All rights reserved.

Exploring movement and energy in human P-glycoprotein conformational rearrangement.

PubMed

Zhang, Yue; Gong, Weikang; Wang, Yan; Liu, Yang; Li, Chunhua

2018-04-24

Human P-glycoprotein (P-gp), a kind of ATP-Binding Cassette transporter, can export a diverse variety of anti-cancer drugs out of the tumor cell. Its overexpression is one of the main reasons for the multidrug resistance (MDR) of tumor cells. It has been confirmed that during the substrate transport process, P-gp experiences a large-scale structural rearrangement from the inward- to outward-facing states. However, the mechanism of how the nucleotide-binding domains (NBDs) control the transmembrane domains (TMDs) to open towards the periplasm in the outward-facing state has not yet been fully characterized. Herein, targeted molecular dynamics simulations were performed to explore the conformational rearrangement of human P-gp. The results show that the allosteric process proceeds in a coupled way, and first the transition is driven by the NBDs, and then transmitted to the cytoplasmic parts of TMDs, finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement, which mainly occurs in xy plane and ensures the formation of the correct ATP-binding pockets. The analyses on the interaction energies between the six structure segments (cICLs) from the TMDs and NBDs reveal that their subtle energy differences play an important role in causing the periplasmic parts of the transmembrane helices to separate from each other in the established directions and in appropriate amplitudes. This conclusion can explain the two experimental phenomena about human P-gp in some extent. These studies have provided a detailed exploration into human P-gp rearrangement process and given an energy insight into the TMD reorientation during P-gp transition.

Understanding the conformation transition in the activation pathway of β2 adrenergic receptor via a targeted molecular dynamics simulation.

PubMed

Xiao, Xiuchan; Zeng, Xiaojun; Yuan, Yuan; Gao, Nan; Guo, Yanzhi; Pu, Xuemei; Li, Menglong

2015-01-28

G protein coupled receptors (GPCRs) play a crucial role in regulating signal recognition and transduction through their activation. The conformation transition in the activation pathway is of particular importance for their function. However, it has been poorly elucidated due to experimental difficulties in determining the conformations and the time limitation of conventional molecular dynamics (CMD) simulation. Thus, in this work, we employed a targeted molecular dynamic (TMD) simulation to study the activation process from an inactive structure to a fully active one for β2 adrenergic receptor (β2AR). As a reference, 110 ns CMD simulations on wild β2AR and its D130N mutant were also carried out. TMD results show that there is at least an intermediate conformation cluster in the activation process, evidenced by the principal component analysis and the structural and dynamic differences of some important motifs. It is noteworthy that the activation of the ligand binding site lags the G-protein binding site, displaying uncoupled correlation. Comparisons between the CMD and TMD results show that the D130N mutation significantly speeds up ICL2 and key ionic lock to enter into the intermediate state, which to some extent facilitates the activation involved in the NPxxY, DRY region and the separation between TM3 and TM6. However, the contribution from the D130N mutation to the activation of the ligand binding site could not be observed within the scale of 110 ns time. These observations could provide novel insights into previous studies for better understanding of the activation mechanism for β2AR.

Cucumber Cotyledon Lipoxygenase during Postgerminative Growth. Its Expression and Action on Lipid Bodies

PubMed Central

Matsui, Kenji; Hijiya, Kohko; Tabuchi, Yutaka; Kajiwara, Tadahiko

1999-01-01

In cucumber (Cucumis sativus), high lipoxygenase-1 (LOX-1) activity has been detected in the soluble fraction prepared from cotyledons of germinating seeds, and the involvement of this enzyme in lipid turnover has been suggested (K. Matsui, M. Irie, T. Kajiwara, A. Hatanaka [1992] Plant Sci 85: 23–32; I. Fuessner, C. Wasternack, H. Kindl, H. Kühn [1995] Proc Natl Acad Sci USA 92: 11849–11853). In this study we have investigated the expression of the gene lox-1, corresponding to the LOX-1 enzyme. LOX-1 expression is highly coordinated with that of a typical glyoxysomal enzyme, isocitrate lyase, during the postgerminative stage of cotyledon development. In contrast, although icl transcripts accumulated in tissue during in vitro senescence, no accumulation of lox-1 mRNA could be observed, suggesting that lox-1 plays a specialized role in fat mobilization. LOX-1 is also known to be a major lipid body protein. The partial peptide sequences of purified LOX-1 and lipid body LOX-1 entirely coincided with that deduced from the lox-1 cDNA sequence. The data strongly suggest that LOX-1 and lipid body LOX-1 are derived from a single gene and that LOX-1 can exist both in the cytosol and on the lipid bodies. We constructed an in vitro oxygenation system to address the mechanism of this dual localization and to investigate the action of LOX-1 on lipids in the lipid bodies. LOX-1 cannot act on the lipids in intact lipid bodies, although degradation of lipid body proteins, either during seedling growth or by treatment with trypsin, allows lipid bodies to become susceptible to LOX-1. We discuss the role of LOX-1 in fat mobilization and its mechanism of action. PMID:10198086

Synthesis and antitumor activity evaluation of a novel combi-nitrosourea prodrug: Designed to release a DNA cross-linking agent and an inhibitor of O(6)-alkylguanine-DNA alkyltransferase.

PubMed

Sun, Guohui; Zhang, Na; Zhao, Lijiao; Fan, Tengjiao; Zhang, Shufen; Zhong, Rugang

2016-05-01

The drug resistance of CENUs induced by O(6)-alkylguanine-DNA alkyltransferase (AGT), which repairs the O(6)-alkylated guanine and subsequently inhibits the formation of dG-dC cross-links, hinders the application of CENU chemotherapies. Therefore, the discovery of CENU analogs with AGT inhibiting activity is a promising approach leading to novel CENU chemotherapies with high therapeutic index. In this study, a new combi-nitrosourea prodrug 3-(3-(((2-amino-9H-purin-6-yl)oxy)methyl)benzyl)-1-(2-chloroethyl)-1-nitrosourea (6), designed to release a DNA cross-linking agent and an inhibitor of AGT, was synthesized and evaluated for its antitumor activity and ability to induce DNA interstrand cross-links (ICLs). The results indicated that 6 exhibited higher cytotoxicity against mer(+) glioma cells compared with ACNU, BCNU, and their respective combinations with O(6)-benzylguanine (O(6)-BG). Quantifications of dG-dC cross-links induced by 6 were performed using HPLC-ESI-MS/MS. Higher levels of dG-dC cross-link were observed in 6-treated human glioma SF763 cells (mer(+)), whereas lower levels of dG-dC cross-link were observed in 6-treated calf thymus DNA, when compared with the groups treated with BCNU and ACNU. The results suggested that the superiority of 6 might result from the AGT inhibitory moiety, which specifically functions in cells with AGT activity. Molecular docking studies indicated that five hydrogen bonds were formed between the O(6)-BG analogs released from 6 and the five residues in the active pocket of AGT, which provided a reasonable explanation for the higher AGT-inhibitory activity of 6 than O(6)-BG. Copyright © 2016 Elsevier Ltd. All rights reserved.

Crystal structure of the adenosine A 2A receptor bound to an antagonist reveals a potential allosteric pocket

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Bingfa; Bachhawat, Priti; Chu, Matthew Ling-Hon

The adenosine A2A receptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson’s disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2A receptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyl D-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A2A receptor with a cytochrome b562-RIL (BRIL) fusion (A2AR–BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phasemore » diffusion. Whereas A2AR–BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1–bound A2AR–BRIL prevented formation of the lattice observed with the ZM241385–bound receptor. The crystals grew with a type II crystal lattice in contrast to the typical type I packing seen from membrane protein structures crystallized in LCP. Cmpd-1 binds in a position that overlaps with the native ligand adenosine, but its methoxyphenyl group extends to an exosite not previously observed in other A2AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr91.35 and Tyr2717.36, which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other A2AR structures, highlighting flexibility in the binding pocket that may facilitate the development of A2AR-selective compounds for the treatment of Parkinson’s disease.« less

Estrogenic compounds inhibit gap junctional intercellular communication in mouse Leydig TM3 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iwase, Yumiko; Fukata, Hideki; Mori, Chisato

2006-05-01

Some estrogenic compounds are reported to cause testicular disorders in humans and/or experimental animals by direct action on Leydig cells. In carcinogenesis and normal development, gap junctional intercellular communication (GJIC) plays an essential role in maintaining homeostasis. In this study, we examine the effects of diethylstilbestrol (DES, a synthetic estrogen), 17{beta}-estradiol (E{sub 2}, a natural estrogen), and genistein (GEN, a phytoestrogen) on GJIC between mouse Leydig TM3 cells using Lucifer yellow microinjection. The three compounds tested produced GJIC inhibition in the TM3 cells after 24 h. Gradually, 10 {mu}M DES began to inhibit GJIC for 24 h and this effectmore » was observed until 72 h. On the other hand, both 20 {mu}M E{sub 2} and 25 {mu}M GEN rapidly inhibited GJIC in 6 h and 2 h, respectively. The effects continued until 24 h, but weakened by 72 h. Furthermore, a combined effect at {mu}M level between DES and E{sub 2} on GJIC inhibition was observed, but not between GEN and E{sub 2}. DES and E{sub 2} showed GJIC inhibition at low dose levels (nearly physiological estrogen levels) after 72 h, but GEN did not. DES-induced GJIC inhibition at 10 pM and 10 {mu}M was completely counteracted by ICI 182,780 (ICl), an estrogen receptor antagonist. On the other hand, the inhibitory effects on GJIC with E{sub 2} (10 pM and 20 {mu}M) and GEN (25 {mu}M) were partially blocked by ICI or calphostin C, a protein kinase C (PKC) inhibitor, and were completely blocked by the combination of ICI and calphostin C. These results demonstrate that DES inhibits GJIC between Leydig cells via the estrogen receptor (ER), and that E{sub 2} and GEN inhibit GJIC via ER and PKC. These estrogenic compounds may have different individual nongenotoxic mechanism including PKC pathway on testicular carcinogenesis or development.« less

Msn2p and Msn4p Control a Large Number of Genes Induced at the Diauxic Transition Which Are Repressed by Cyclic AMP in Saccharomyces cerevisiae

PubMed Central

Boy-Marcotte, Emmanuelle; Perrot, Michel; Bussereau, Françoise; Boucherie, Hélian; Jacquet, Michel

1998-01-01

The multicopy suppressors of the snf1 defect, Msn2p and Msn4p transcription factors (Msn2/4p), activate genes through the stress-responsive cis element (CCCCT) in response to various stresses. This cis element is also the target for repression by the cyclic AMP (cAMP)-signaling pathway. We analyzed the two-dimensional gel electrophoresis pattern of protein synthesis of the msn2 msn4 double mutant and compared it with that of the wild-type strain during exponential growth phase and at the diauxic transition. Thirty-nine gene products (including those of ALD3, GDH3, GLK1, GPP2, HSP104, HXK1, PGM2, SOD2, SSA3, SSA4, TKL2, TPS1, and YBR149W) are dependent upon Msn2/4p for their induction at the diauxic transition. The expression of all these genes is repressed by cAMP. Thirty other genes identified during this study are still inducible in the mutant. A subset of these genes were found to be superinduced at the diauxic transition, and others were subject to cAMP repression (including ACH1, ADH2, ALD6, ATP2, GPD1, ICL1, and KGD2). We conclude from this analysis that Msn2/4p control a large number of genes induced at the diauxic transition but that other, as-yet-uncharacterized regulators, also contribute to this response. In addition, we show here that cAMP repression applies to both Msn2/4p-dependent and -independent control of gene expression at the diauxic shift. Furthermore, the fact that all the Msn2/4p gene targets are subject to cAMP repression suggests that these regulators could be targets for the cAMP-signaling pathway. PMID:9495741

High sensitivity stand-off detection and quantification of chemical mixtures using an active coherent laser spectrometer (ACLaS)

NASA Astrophysics Data System (ADS)

MacLeod, Neil A.; Weidmann, Damien

2016-05-01

High sensitivity detection, identification and quantification of chemicals in a stand-off configuration is a highly sought after capability across the security and defense sector. Specific applications include assessing the presence of explosive related materials, poisonous or toxic chemical agents, and narcotics. Real world field deployment of an operational stand-off system is challenging due to stringent requirements: high detection sensitivity, stand-off ranges from centimeters to hundreds of meters, eye-safe invisible light, near real-time response and a wide chemical versatility encompassing both vapor and condensed phase chemicals. Additionally, field deployment requires a compact, rugged, power efficient, and cost-effective design. To address these demanding requirements, we have developed the concept of Active Coherent Laser Spectrometer (ACLaS), which can be also described as a middle infrared hyperspectral coherent lidar. Combined with robust spectral unmixing algorithms, inherited from retrievals of information from high-resolution spectral data generated by satellitebased spectrometers, ACLaS has been demonstrated to fulfil the above-mentioned needs. ACLaS prototypes have been so far developed using quantum cascade lasers (QCL) and interband cascade lasers (ICL) to exploit the fast frequency tuning capability of these solid state sources. Using distributed feedback (DFB) QCL, demonstration and performance analysis were carried out on narrow-band absorbing chemicals (N2O, H2O, H2O2, CH4, C2H2 and C2H6) at stand-off distances up to 50 m using realistic non cooperative targets such as wood, painted metal, and bricks. Using more widely tunable external cavity QCL, ACLaS has also been demonstrated on broadband absorbing chemicals (dichloroethane, HFC134a, ethylene glycol dinitrate and 4-nitroacetanilide solid) and on complex samples mixing narrow-band and broadband absorbers together in a realistic atmospheric background.

Volatile composition of microinclusions in diamonds from the Panda kimberlite, Canada: Implications for chemical and isotopic heterogeneity in the mantle

NASA Astrophysics Data System (ADS)

Burgess, Ray; Cartigny, Pierre; Harrison, Darrell; Hobson, Emily; Harris, Jeff

2009-03-01

In order to better investigate the compositions and the origins of fluids associated with diamond growth, we have carried-out combined noble gas (He and Ar), C and N isotope, K, Ca and halogen (Cl, Br, I) determinations on fragments of individual microinclusion-bearing diamonds from the Panda kimberlite, North West Territories, Canada. The fluid concentrations of halogens and noble gases in Panda diamonds are enriched by several orders of magnitude over typical upper mantle abundances. However, noble gas, C and N isotopic ratios ( 3He/ 4He = 4-6 Ra, 40Ar/ 36Ar = 20,000-30,000, δ 13C = -4.5‰ to -6.9‰ and δ 15N = -1.2‰ to -8.8‰) are within the worldwide range determined for fibrous diamonds and similar to the mid ocean ridge basalt (MORB) source value. The high 36Ar content of the diamonds (>1 × 10 -9 cm 3/g) is at least an order of magnitude higher than any previously reported mantle sample and enables the 36Ar content of the subcontinental lithospheric mantle to be estimated at ˜0.6 × 10 -12 cm 3/g, again similar to estimates for the MORB source. Three fluid types distinguished on the basis of Ca-K-Cl compositions are consistent with carbonatitic, silicic and saline end-members identified in previous studies of diamonds from worldwide sources. These fluid end-members also have distinct halogen ratios (Br/Cl and I/Cl). The role of subducted seawater-derived halogens, originally invoked to explain some of the halogen ratio variations in diamonds, is not considered an essential component in the formation of the fluids. In contrast, it is considered that large halogen fractionation of a primitive mantle ratio occurs during fluid-melt partitioning in forming silicic fluids, and during separation of an immiscible saline fluid.

Chloride currents in cones modify feedback from horizontal cells to cones in goldfish retina

PubMed Central

Endeman, Duco; Fahrenfort, Iris; Sjoerdsma, Trijntje; Steijaert, Marvin; ten Eikelder, Huub; Kamermans, Maarten

2012-01-01

In neuronal systems, excitation and inhibition must be well balanced to ensure reliable information transfer. The cone/horizontal cell (HC) interaction in the retina is an example of this. Because natural scenes encompass an enormous intensity range both in temporal and spatial domains, the balance between excitation and inhibition in the outer retina needs to be adaptable. How this is achieved is unknown. Using electrophysiological techniques in the isolated retina of the goldfish, it was found that opening Ca2+-dependent Cl− channels in recorded cones reduced the size of feedback responses measured in both cones and HCs. Furthermore, we show that cones express Cl− channels that are gated by GABA released from HCs. Similar to activation of ICl(Ca), opening of these GABA-gated Cl− channels reduced the size of light-induced feedback responses both in cones and HCs. Conversely, application of picrotoxin, a blocker of GABAA and GABAC receptors, had the opposite effect. In addition, reducing GABA release from HCs by blocking GABA transporters also led to an increase in the size of feedback. Because the independent manipulation of Ca2+-dependent Cl− currents in individual cones yielded results comparable to bath-applied GABA, it was concluded that activation of either Cl− current by itself is sufficient to reduce the size of HC feedback. However, additional effects of GABA on outer retinal processing cannot be excluded. These results can be accounted for by an ephaptic feedback model in which a cone Cl− current shunts the current flow in the synaptic cleft. The Ca2+-dependent Cl− current might be essential to set the initial balance between the feedforward and the feedback signals active in the cone HC synapse. It prevents that strong feedback from HCs to cones flood the cone with Ca2+. Modulation of the feedback strength by GABA might play a role during light/dark adaptation, adjusting the amount of negative feedback to the signal to noise ratio of the cone output. PMID:22890705

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

PubMed Central

Childers, Delma S.; Raziunaite, Ingrida; Mol Avelar, Gabriela; Mackie, Joanna; Budge, Susan; Stead, David; Gow, Neil A. R.; Lenardon, Megan D.; Ballou, Elizabeth R.; MacCallum, Donna M.; Brown, Alistair J. P.

2016-01-01

Efficient carbon assimilation is critical for microbial growth and pathogenesis. The environmental yeast Saccharomyces cerevisiae is “Crabtree positive”, displaying a rapid metabolic switch from the assimilation of alternative carbon sources to sugars. Following exposure to sugars, this switch is mediated by the transcriptional repression of genes (carbon catabolite repression) and the turnover (catabolite inactivation) of enzymes involved in the assimilation of alternative carbon sources. The pathogenic yeast Candida albicans is Crabtree negative. It has retained carbon catabolite repression mechanisms, but has undergone posttranscriptional rewiring such that gluconeogenic and glyoxylate cycle enzymes are not subject to ubiquitin-mediated catabolite inactivation. Consequently, when glucose becomes available, C. albicans can continue to assimilate alternative carbon sources alongside the glucose. We show that this metabolic flexibility promotes host colonization and virulence. The glyoxylate cycle enzyme isocitrate lyase (CaIcl1) was rendered sensitive to ubiquitin-mediated catabolite inactivation in C. albicans by addition of a ubiquitination site. This mutation, which inhibits lactate assimilation in the presence of glucose, reduces the ability of C. albicans cells to withstand macrophage killing, colonize the gastrointestinal tract and cause systemic infections in mice. Interestingly, most S. cerevisiae clinical isolates we examined (67%) have acquired the ability to assimilate lactate in the presence of glucose (i.e. they have become Crabtree negative). These S. cerevisiae strains are more resistant to macrophage killing than Crabtree positive clinical isolates. Moreover, Crabtree negative S. cerevisiae mutants that lack Gid8, a key component of the Glucose-Induced Degradation complex, are more resistant to macrophage killing and display increased virulence in immunocompromised mice. Thus, while Crabtree positivity might impart a fitness advantage for yeasts in environmental niches, the more flexible carbon assimilation strategies offered by Crabtree negativity enhance the ability of yeasts to colonize and infect the mammalian host. PMID:27073846

Methylarcula marina gen. nov., sp. nov. and Methylarcula terricola sp. nov.: novel aerobic, moderately halophilic, facultatively methylotrophic bacteria from coastal saline environments.

PubMed

Doronina, N V; Trotsenko, Y A; Tourova, T P

2000-09-01

A new genus, Methylarcula, with two new species, Methylarcula marina and Methylarcula terricola, are proposed for strains h1T and h37T of moderately halophilic facultatively methylotrophic bacteria isolated from the coastal saline habitats. These methylobacteria are aerobic, Gram-negative, asporogenous, non-motile, colourless rods that multiply by binary fission. Their cellular fatty acids profiles consist primarily of straight-chain unsaturated (C18:1; 70-80%), saturated (C18:0; 14-16%) and cyclopropane (C19:0; 5-6%) acids. The major ubiquinone is Q-10. The dominant phospholipids are phosphatidylethanolamine and phosphatidylcholine. Both strains could use methylamine, some sugars and organic acids as carbon and energy sources. They grew well under optimal conditions (29-35 degrees C, pH 7.5-8.5, 0.5-1.0 M NaCl) and accumulated intracellularly poly-beta-hydroxybutyrate and the compatible solute ectoine. The ectoine pool was found to increase upon increasing the external NaCl concentration and accounted for 18% of the dry cellular weight. Both strains oxidized methylamine by the N-methylglutamate (N-MG) pathway enzymes (gamma-glutamylmethylamide synthetase/lyase and N-MG synthetase/lyase) to formaldehyde and assimilated it via the icl- serine pathway. The DNA G+C content was 60-4 mol% for Methylarcula marina h1T and 57.1 mol% for Methylarcula terricola h37T. The DNA-DNA hybridization value between strains hl and h37 was 25-30%, although they had a low level of DNA relatedness (5-7%) with the type strains of the serine pathway methylobacteria belonging to the genera Methylobacterium, Aminobacter, Methylorhabdus and Methylopila. A comparative 16S rDNA sequence-based phylogenetic analysis placed the two species of Methylarcula into a separate branch of the alpha-3 subclass of the Proteobacteria. The type strains of the new species are Methylarcula marina h1T (= VKM B-2159T) and Methylarcula terricola h37T (= VKM B-2160T).

Mutations in Alternative Carbon Utilization Pathways in Candida albicans Attenuate Virulence and Confer Pleiotropic Phenotypes▿

PubMed Central

Ramírez, Melissa A.; Lorenz, Michael C.

2007-01-01

The interaction between Candida albicans and cells of the innate immune system is a key determinant of disease progression. Transcriptional profiling has revealed that C. albicans has a complex response to phagocytosis, much of which is similar to carbon starvation. This suggests that nutrient limitation is a significant stress in vivo, and we have shown that glyoxylate cycle mutants are less virulent in mice. To examine whether other aspects of carbon metabolism are important in vivo during an infection, we have constructed strains lacking FOX2 and FBP1, which encode key components of fatty acid β-oxidation and gluconeogenesis, respectively. As expected, fox2Δ mutants failed to utilize several fatty acids as carbon sources. Surprisingly, however, these mutants also failed to grow in the presence of several other carbon sources, whose assimilation is independent of β-oxidation, including ethanol and citric acid. Mutants lacking the glyoxylate enzyme ICL1 also had more severe carbon utilization phenotypes than were expected. These results suggest that the regulation of alternative carbon metabolism in C. albicans is significantly different from that in other fungi. In vivo, fox2Δ mutants show a moderate but significant reduction in virulence in a mouse model of disseminated candidiasis, while disruption of the glyoxylate cycle or gluconeogenesis confers a severe attenuation in this model. These data indicate that C. albicans often encounters carbon-poor conditions during growth in the host and that the ability to efficiently utilize multiple nonfermentable carbon sources is a virulence determinant. Consistent with this in vivo requirement, C. albicans uniquely regulates carbon metabolism in a more integrated manner than in Saccharomyces cerevisiae, such that defects in one part of the machinery have wider impacts than expected. These aspects of alternative carbon metabolism may then be useful as targets for therapeutic intervention. PMID:17158734

Direct-Potential (dpf) Analysis for the a 3Π1-X 1Σ+ System of I35/37Cl.

NASA Astrophysics Data System (ADS)

Kobayashi, Shinji; Nishimiya, Nobuo; Yukiya, Tokio; Suzuki, Masao; Le Roy, Robert J.

2016-06-01

The goal of this research is to obtain an optimal, portable, global description of, and summary of the dynamical properties of, the A 3Π1 and X 1Σ+ states of I35/37Cl, by using `direct potential fits' (DPFs) to all of the available spectroscopic data for this system to determine optimal analytic potential energy functions for these two states that represent all of those data (on average), within the experimental uncertainties. The DPF method compares observed spectroscopic data with synthetic data generated by solving the radial Schrödinger equation for the upper and lower level of every observed transition for some parameterized analytic potential function(s), and using least-squares fits to the data to optimize those parameters. The present work uses the Morse/Long-Range (MLR) potential function form because it is very flexible, can incorporate the correct theoretically known inverse-power-sum long-range behaviour, is everywhere continuous and differentiable to all orders, and has robust extrapolation properties at both large and small distances. The DPF approach also tends to require fewer fitting parameters than do traditional Dunham analyses, as well as having much more robust extrapolation properties in both the v and J domains. The present work combines the data for the A 3Π1 and X 1Σ+ states obtained in 1980 by Coxon et al. using UV and near-infrared grating spectrometers, with our measurements in the 0.7-0.8μm region, obtained using a CW Ti:Sapphire Ring Laser. The results of this study and our new fully analytic potential energy functions for the A 3Π1 and X 1Σ+ states of ICl will be presented. J.A. Coxon, R.M. Gordon and M.A. Wickramaaratchi, J. Mol. Spectrosc. 79 (1980) 363 and 380. T.Yukiya, N. Nishimiya and M. Suzuki, J. Mol. Spectrosc. 269 (2011) 193.

Mycobacterium tuberculosis Uses Host Triacylglycerol to Accumulate Lipid Droplets and Acquires a Dormancy-Like Phenotype in Lipid-Loaded Macrophages

PubMed Central

Daniel, Jaiyanth; Sirakova, Tatiana D.; Kolattukudy, Pappachan E.

2011-01-01

Two billion people are latently infected with Mycobacterium tuberculosis (Mtb). Mtb-infected macrophages are likely to be sequestered inside the hypoxic environments of the granuloma and differentiate into lipid-loaded macrophages that contain triacylglycerol (TAG)-filled lipid droplets which may provide a fatty acid-rich host environment for Mtb. We report here that human peripheral blood monocyte-derived macrophages and THP-1 derived macrophages incubated under hypoxia accumulate Oil Red O-staining lipid droplets containing TAG. Inside such hypoxic, lipid-loaded macrophages, nearly half the Mtb population developed phenotypic tolerance to isoniazid, lost acid-fast staining and accumulated intracellular lipid droplets. Dual-isotope labeling of macrophage TAG revealed that Mtb inside the lipid-loaded macrophages imports fatty acids derived from host TAG and incorporates them intact into Mtb TAG. The fatty acid composition of host and Mtb TAG were nearly identical suggesting that Mtb utilizes host TAG to accumulate intracellular TAG. Utilization of host TAG by Mtb for lipid droplet synthesis was confirmed when fluorescent fatty acid-labeled host TAG was utilized to accumulate fluorescent lipid droplets inside the pathogen. Deletion of the Mtb triacylglycerol synthase 1 (tgs1) gene resulted in a drastic decrease but not a complete loss in both radiolabeled and fluorescent TAG accumulation by Mtb suggesting that the TAG that accumulates within Mtb is generated mainly by the incorporation of fatty acids released from host TAG. We show direct evidence for the utilization of the fatty acids from host TAG for lipid metabolism inside Mtb. Taqman real-time PCR measurements revealed that the mycobacterial genes dosR, hspX, icl1, tgs1 and lipY were up-regulated in Mtb within hypoxic lipid loaded macrophages along with other Mtb genes known to be associated with dormancy and lipid metabolism. PMID:21731490

Analytical evaluation of the ADAMS™ A1c HA 8180 thalassemia mode high-pressure liquid chromatography analyser for the measurement of HbA2 and HbF.

PubMed

Urrechaga, E

2016-12-01

ADAMS ™ A1cHA-8180T is a HPLC system; within 3.5 min, it quantifies HbF, HbA 2 , and HbA 0 and flags abnormal peaks. We evaluate its analytical performance for routine estimation of HbA 2 and HbF, and critical tests were performed for identifying β-thalassemia carriers. Trueness imprecision, carry over, linearity, and effect of anemia were evaluated according to ICLH, ICLS, or manufacture's guidelines. Comparison (ADAMS ™ A1c HA-8160T) was performed by running 400 samples from healthy subjects, 30 alpha and 80 beta carriers (range: 1.9-5.7 %). Trueness - HbA 2 2.7 %, bias 0.81 %; HbA 2 5.8 %, bias 0.38 %. HbA 2 4.0% is not affected by Hb in the range 221-40 g/L. Carry over was negligible. Within run: normal control - CV 1.5 %, high control - CV 0.9 %.Within laboratory: normal control - total CV% 1.59%; high control - 0.92 %. Linearity - y = 1.034x - 0.17, R 2  = 0.998 (range: 2.8-4.8%).Method comparison - y = 0.93x + 0.22, R 2  = 0.997. HbF imprecision CVs between 0.66 and 1.24% and trueness between 0 and 2.8%. Linearity - y = 1.088x - 0.27, R 2  = 0.999 (0.1-5.7%). ADAMS ™ A1c HA-8180T provides a rapid and reliable separation of HbA 2 . The measurement is accurate and reproducible, which is needed because of the slight difference between normal and pathological values. The gap in HbA 2 values between normal subjects and β-thalassemia carriers makes this an appropriate method for rapid screening for carriers. © 2016 John Wiley & Sons Ltd.

Halogens in chondritic meteorites and terrestrial accretion

NASA Astrophysics Data System (ADS)

Clay, Patricia L.; Burgess, Ray; Busemann, Henner; Ruzié-Hamilton, Lorraine; Joachim, Bastian; Day, James M. D.; Ballentine, Christopher J.

2017-11-01

Volatile element delivery and retention played a fundamental part in Earth’s formation and subsequent chemical differentiation. The heavy halogens—chlorine (Cl), bromine (Br) and iodine (I)—are key tracers of accretionary processes owing to their high volatility and incompatibility, but have low abundances in most geological and planetary materials. However, noble gas proxy isotopes produced during neutron irradiation provide a high-sensitivity tool for the determination of heavy halogen abundances. Using such isotopes, here we show that Cl, Br and I abundances in carbonaceous, enstatite, Rumuruti and primitive ordinary chondrites are about 6 times, 9 times and 15-37 times lower, respectively, than previously reported and usually accepted estimates. This is independent of the oxidation state or petrological type of the chondrites. The ratios Br/Cl and I/Cl in all studied chondrites show a limited range, indistinguishable from bulk silicate Earth estimates. Our results demonstrate that the halogen depletion of bulk silicate Earth relative to primitive meteorites is consistent with the depletion of lithophile elements of similar volatility. These results for carbonaceous chondrites reveal that late accretion, constrained to a maximum of 0.5 ± 0.2 per cent of Earth’s silicate mass, cannot solely account for present-day terrestrial halogen inventories. It is estimated that 80-90 per cent of heavy halogens are concentrated in Earth’s surface reservoirs and have not undergone the extreme early loss observed in atmosphere-forming elements. Therefore, in addition to late-stage terrestrial accretion of halogens and mantle degassing, which has removed less than half of Earth’s dissolved mantle gases, the efficient extraction of halogen-rich fluids from the solid Earth during the earliest stages of terrestrial differentiation is also required to explain the presence of these heavy halogens at the surface. The hydropilic nature of halogens, whereby they track with water, supports this requirement, and is consistent with volatile-rich or water-rich late-stage terrestrial accretion.

Inverse compton light source: a compact design proposal

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deitrick, Kirsten Elizabeth

In the last decade, there has been an increasing demand for a compact Inverse Compton Light Source (ICLS) which is capable of producing high-quality X-rays by colliding an electron beam and a high-quality laser. It is only in recent years when both SRF and laser technology have advanced enough that compact sources can approach the quality found at large installations such as the Advanced Photon Source at Argonne National Laboratory. Previously, X-ray sources were either high flux and brilliance at a large facility or many orders of magnitude lesser when produced by a bremsstrahlung source. A recent compact source wasmore » constructed by Lyncean Technologies using a storage ring to produce the electron beam used to scatter the incident laser beam. By instead using a linear accelerator system for the electron beam, a significant increase in X-ray beam quality is possible, though even subsequent designs also featuring a storage ring offer improvement. Preceding the linear accelerator with an SRF reentrant gun allows for an extremely small transverse emittance, increasing the brilliance of the resulting X-ray source. In order to achieve sufficiently small emittances, optimization was done regarding both the geometry of the gun and the initial electron bunch distribution produced off the cathode. Using double-spoke SRF cavities to comprise the linear accelerator allows for an electron beam of reasonable size to be focused at the interaction point, while preserving the low emittance that was generated by the gun. An aggressive final focusing section following the electron beam's exit from the accelerator produces the small spot size at the interaction point which results in an X-ray beam of high flux and brilliance. Taking all of these advancements together, a world class compact X-ray source has been designed. It is anticipated that this source would far outperform the conventional bremsstrahlung and many other compact ICLSs, while coming closer to performing at the levels found at large facilities than ever before. The design process, including the development between subsequent iterations, is presented here in detail, with the simulation results for this groundbreaking X-ray source.« less

Neurotoxicological effects of nicotine on the embryonic development of cerebellar cortex of chick embryo during various stages of incubation.

PubMed

El-Beltagy, Abd El-Fattah B M; Abou-El-Naga, Amoura M; Sabry, Dalia M

2015-10-01

Long-acting nicotine is known to exert pathological effects on almost all tissues including the cerebellar cortex. The present work was designed to elucidate the effect of nicotine on the development of cerebellar cortex of chick embryo during incubation period. The fertilized eggs of hen (Gallus gallus domesticus) were injected into the air space by a single dose of long acting nicotine (1.6 mg/kg/egg) at the 4th day of incubation. The embryos were taken out of the eggs on days 8, 12 and 16 of incubation. The cerebellum of the control and treated embryos at above ages were processed for histopathological examination. The TEM were examined at 16th day of incubation. The results of the present study revealed that, exposure to long-acting nicotine markedly influence the histogenesis of cerebellar cortex of chick embryo during the incubation period. At 8th day of incubation, nicotine delayed the differentiation of the cerebellar analge; especially the external granular layer (EGL) and inner cortical layer (ICL). Furthermore, at 12th day of incubation, the cerebellar foliation was irregular and the Purkinje cells not recognized. By 16th day of incubation, the cerebellar foliations were irregular with interrupted cerebellar cortex and irregular arrangement of Purkinje cells. Immunohistochemical analysis for antibody P53 protein revealed that the cerebellar cortex in all stages of nicotine treated groups possessed a moderate to weak reaction for P53 protein however; this reaction was markedly stronger in the cerebellar cortex of control groups. Moreover, the flow cytometric analysis confirmed that the percentage of apoptosis in control group was significantly higher compared with that of nicotine treated group. At the TEM level, the cerebellar Purkinje cells of 16th day of treated groups showed multiple subcellular alterations in compared with those of the corresponding control group. Such changes represented by appearing of vacuolated mitochondria, cisternal fragmentation of RER, irregular grooves of Golgi tubules. Also, multiple cytoplasmic vacuoles and aggregation of Nissl granules were recorded around pyknotic nucleus. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of the anti-neoplastic drug doxorubicin on XPD-mutated DNA repair-deficient human cells.

PubMed

Saffi, Jenifer; Agnoletto, Mateus H; Guecheva, Temenouga N; Batista, Luís F Z; Carvalho, Helotonio; Henriques, João A P; Stary, Anne; Menck, Carlos F M; Sarasin, Alain

2010-01-02

Doxorubicin (DOX), a member of the anthracycline group, is a widely used drug in cancer therapy. The mechanisms of DOX action include topoisomerase II-poisoning, free radical release, DNA adducts and interstrand cross-link (ICL) formation. Nucleotide excision repair (NER) is involved in the removal of helix-distorting lesions and chemical adducts, however, little is known about the response of NER-deficient cell lines to anti-tumoral drugs like DOX. Wild type and XPD-mutated cells, harbouring mutations in different regions of this gene and leading to XP-D, XP/CS or TTD diseases, were treated with this drug and analyzed for cell cycle arrest and DNA damage by comet assay. The formation of DSBs was also investigated by determination of gammaH2AX foci. Our results indicate that all three NER-deficient cell lines tested are more sensitive to DOX treatment, when compared to wild type cells or XP cells complemented by the wild type XPD cDNA, suggesting that NER is involved in the removal of DOX-induced lesions. The cell cycle analysis showed the characteristic G2 arrest in repair-proficient MRC5 cell line after DOX treatment, whereas the repair-deficient cell lines presented significant increase in sub-G1 fraction. The NER-deficient cell lines do not show different patterns of DNA damage formation as assayed by comet assay and phosphorylated H2AX foci formation. Knock-down of topoisomerase IIalpha with siRNA leads to increased survival in both MRC5 and XP cells, however, XP cell line still remained significantly more sensitive to the treatment by DOX. Our study suggests that the enhanced sensitivity is due to DOX-induced DNA damage that is subject to NER, as we observed decreased unscheduled DNA synthesis in XP-deficient cells upon DOX treatment. Furthermore, the complementation of the XPD-function abolished the observed sensitivity at lower DOX concentrations, suggesting that the XPD helicase activity is involved in the repair of DOX-induced lesions. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Portable nitrous oxide sensor for understanding agricultural and soil emissions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stanton, Alan; Zondlo, Mark; Gomez, Anthony

Nitrous oxide (N2O) is the third most important greenhouse gas (GHG,) with an atmospheric lifetime of ~114 years and a global warming impact ~300 times greater than that of carbon dioxide. The main cause of nitrous oxide’s atmospheric increase is anthropogenic emissions, and over 80% of the current global anthropogenic flux is related to agriculture, including associated land-use change. An accurate assessment of N2O emissions from agriculture is vital not only for understanding the global N2O balance and its impact on climate but also for designing crop systems with lower GHG emissions. Such assessments are currently hampered by the lackmore » of instrumentation and methodologies to measure ecosystem-level fluxes at appropriate spatial and temporal scales. Southwest Sciences and Princeton University are developing and testing new open-path eddy covariance instrumentation for continuous and fast (10 Hz) measurement of nitrous oxide emissions. An important advance, now being implemented, is the use of new mid-infrared laser sources that enable the development of exceptionally low power (<10 W) compact instrumentation that can be used even in remote sites lacking in power. The instrumentation will transform the ability to measure and understand ecosystem-level nitrous oxide fluxes. The Phase II results included successful extended field testing of prototype flux instruments, based on quantum cascade lasers, in collaboration with Michigan State University. Results of these tests demonstrated a flux detection limit of 5 µg m-2 s-1 and showed excellent agreement and correlation with measurements using chamber techniques. Initial tests of an instrument using an interband cascade laser (ICL) were performed, verifying that an order of magnitude reduction in instrument power requirements can be realized. These results point toward future improvements and testing leading to introduction of a commercial open path instrument for N2O flux measurements that is truly portable and cost-effective. The technology developed on this project is especially groundbreaking as it could be widely applied across FLUXNET and AmeriFlux sites (>1200 worldwide) for direct measurements of N2O exchange. The technology can be more broadly applied to gas monitoring requirements in industry, environmental monitoring, health and safety, etc.« less

New Palladium-Catalyzed Approaches to Heterocycles and Carbocycles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Qinhua

2004-12-19

The tert-butylimines of o-(1-alkynyl)benzaldehydes and analogous pyridinecarbaldehydes have been cyclized under very mild reaction conditions in the presence of I 2, ICl, PhSeCl, PhSCl and p-O 2NC 6H 4SCl to give the corresponding halogen-, selenium- and sulfur-containing disubstituted isoquinolines and naphthyridines, respectively. Monosubstituted isoquinolines and naphthyridines have been synthesized by the metal-catalyzed ring closure of these same iminoalkynes. This methodology accommodates a variety of iminoalkynes and affords the anticipated heterocycles in moderate to excellent yields. The Pd(II)-catalyzed cyclization of 2-(1-alkynyl)arylaldimines in the presence of various alkenes provides an efficient way to synthesize a variety of 4-(1-alkenyl)-3-arylisoquinolines in moderate to excellentmore » yields. The introduction of an ortho-methoxy group on the arylaldimine promotes the Pd-catalyzed cyclization and stabilizes the resulting Pd(II) intermediate, improving the yields of the isoquinoline products. Highly substituted naphthalenes have been synthesized by the palladium-catalyzed annulation of a variety of internal alkynes, in which two new carbon-carbon bonds are formed in a single step under relatively mild reaction conditions. This method has also been used to synthesize carbazoles, although a higher reaction temperature is necessary. The process involves arylpalladation of the alkyne, followed by intramolecular Heck olefination and double bond isomerization. This method accommodates a variety of functional groups and affords the anticipated highly substituted naphthalenes and carbazoles in good to excellent yields. Novel palladium migratiodarylation methodology for the synthesis of complex fused polycycles has been developed, in which one or more sequential Pd-catalyzed intramolecular migration processes involving C-H activation are employed. The chemistry works best with electron-rich aromatics, which is in agreement with the idea that these palladium-catalyzed C-H activation reactions parallel electrophilic aromatic substitution. A relatively efficient synthesis of cyclopropanes has been developed using palladium-catalyzed C-H activation chemistry, in which two new carbon-carbon bonds are formed in a single step. This method involves the palladium-catalyzed activation of relatively unreactive C-H bonds, and provides a very efficient way to synthesize cyclopropapyrrolo[1,2-a]indoles, analogues of the mitomycin antibiotics.« less

A protocol for an exploratory phase I mixed-methods study of enhanced integrated care for care home residents with advanced dementia: the Compassion Intervention.

PubMed

Elliott, Margaret; Harrington, Jane; Moore, Kirsten; Davis, Sarah; Kupeli, Nuriye; Vickerstaff, Victoria; Gola, Anna; Candy, Bridget; Sampson, Elizabeth L; Jones, Louise

2014-06-17

In the UK approximately 700,000 people are living with, and a third of people aged over 65 will die with, dementia. People with dementia may receive poor quality care towards the end of life. We applied a realist approach and used mixed methods to develop a complex intervention to improve care for people with advanced dementia and their family carers. Consensus on intervention content was achieved using the RAND UCLA appropriateness method and mapped to sociological theories of process and impact. Core components are: (1) facilitation of integrated care, (2) education, training and support, (3) investment from commissioners and care providers. We present the protocol for an exploratory phase I study to implement components 1 and 2 in order to understand how the intervention operates in practice and to assess feasibility and acceptability. An 'Interdisciplinary Care Leader (ICL)' will work within two care homes, alongside staff and associated professionals to facilitate service integration, encourage structured needs assessment, develop the use of personal and advance care plans and support staff training. We will use qualitative and quantitative methods to collect data for a range of outcome and process measures to detect effects on individual residents, family carers, care home staff, the intervention team, the interdisciplinary team and wider systems. Analysis will include descriptive statistics summarising process and care home level data, individual demographic and clinical characteristics and data on symptom burden, clinical events and quality of care. Qualitative data will be explored using thematic analysis. Findings will inform a future phase II trial. Ethical approval was granted (REC reference 14/LO/0370). We shall publish findings at conferences, in peer-reviewed journals, on the Marie Curie Cancer Care website and prepare reports for dissemination by organisations involved with end-of-life care and dementia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Biased distribution of IS629 among strains in different lineages of enterohemorrhagic Escherichia coli serovar O157.

PubMed

Yokoyama, Eiji; Hashimoto, Ruiko; Etoh, Yoshiki; Ichihara, Sachiko; Horikawa, Kazumi; Uchimura, Masako

2011-01-01

The distribution of insertion sequence (IS) 629 among strains of enterohemorrhagic Escherichia coli serovar O157 (O157) was investigated and compared with the strain lineages defined by lineage specific polymorphism assay-6 (LSPA-6) to demonstrate the effectiveness of IS629 analysis for population genetics analysis. Using pulsed-field gel electrophoresis and variable-number tandem repeat typing, 140 strains producing both VT1 and VT2 and 98 strains producing only VT2 were selected from a total of 592 strains isolated from patients and asymptomatic carriers in Chiba Prefecture, Japan, during 2003-2008. By LSPA-6 analysis, six strains had atypical amplicon sizes in their Z5935 loci and five strains had atypical amplicon sizes in their arp-iclR intergenic regions. Sequence analyses of PCR amplified DNAs showed that five of the six loci used for LSPA-6 analysis had tandem repeats and the allele changes were due to changes in the number of tandem repeats. Subculturing and long-term incubation was found to have no detectable effect on the lineages defined by LSPA-6 analysis, demonstrating the robustness of LSPA-6 analysis. Minimum spanning tree analysis reconstruction revealed that strains in lineage I, I/II, and II clustered on separate branches, indicating that the distribution of IS629 was biased among O157 strains in different lineages. Strains with LSPA-6 codes 231111, 211113, and 211114 had atypical amplicon sizes and were clustered in lineage I/II branch, and strains with LSPA-6 codes 212114, 221123, 221223, 222123, 222224, 242123, 252123, and 242222 had atypical amplicon sizes and clustered in lineage II branches. Linkage disequilibrium was observed in strains in every lineage when the standardized index of association was calculated using IS629 distribution data. Therefore, the distribution analysis of IS629 may be effective for population genetics analysis of O157 due to the biased IS629 distribution among strains in the three O157 lineages. Copyright © 2010 Elsevier B.V. All rights reserved.