Alteration of intracellular cysteine and glutathione levels in alveolar macrophages and lymphocytes by diesel exhaust particle exposure.

The purpose of this study was to characterize the effects of diesel exhaust particles (DEP) on thiol regulation in alveolar macrophages (AM) and lymphocytes. We obtained AM and lymph node (thymic and tracheal) cells (LNC) (at different time points) from rats exposed intratracheally to DEP (5 mg/kg) or saline, and measured inflammatory markers, thiol levels, and glutathione reductase (GSH-R) activity. DEP exposure produced significant increases in neutrophils, lactate dehydrogenase, total protein, and albumin content in the lavage fluid. AM from DEP-exposed rats showed a time-dependent increase in intracellular cysteine (CYSH) and GSH. In LNC the intracellular GSH reached peak level by 24 hr, declining toward control levels by 72 hr after exposure. LNC-CYSH and AM-CYSH and GSH were increased at both 24 and 72 hr. Both Sprague-Dawley and Brown Norway rats showed similar trends of responses to DEP exposure as per measurement of the inflammatory markers and thiol changes. AM and, to a lesser degree, LNC were both active in cystine uptake. The DEP exposure stimulated GSH-R activity and increased the conversion of cystine to CYSH in both cell types. The intracellular level of GSH in DEP-exposed AM was moderately increased compared with the saline control, and was further augmented when cells were incubated with cystine. In contrast, the intracellular level of GSH in DEP-exposed LNC was significantly reduced despite the increased CYSH level and GSH-R activity when these cells were cultured for 16 hr. DEP absorbed 23-31% of CYSH, cystine, and GSH, and only 8% of glutathione disulfide when incubated in cell free media. These results indicate that DEP exposure caused lung inflammation and affected thiol levels in both AM and LNC

Decrease in Incidence of Colorectal Cancer Among Individuals 50 Years or Older After Recommendations for Population-based Screening

BACKGROUND & AIMS: The incidence of colorectal cancer (CRC) in the United States is increasing among adults younger than 50 years, but incidence has decreased among older populations after population-based screening was recommended in the late 1980s. Blacks have higher incidence than whites. These patterns have prompted suggestions to lower the screening age for average-risk populations or in blacks. At the same time, there has been controversy over whether reductions in CRC incidence can be attributed to screening. We examined age-related and race-related differences in CRC incidence during a 40-year time period. METHODS: We determined the age-standardized incidence of CRC from 1975 through 2013 by using the population-based Surveillance, Epidemiology, and End Results (SEER) program of cancer registries. We calculated incidence for 5-year age categories (20-24 years through 80-84 years and 85 years or older) for different time periods (1975-1979, 1980-1984, 1985-1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, and 2010-2013), tumor subsite (proximal colon, descending colon, and rectum), and stages at diagnosis (localized, regional, and distant). Analyses were stratified by race (white vs black). RESULTS: There were 450,682 incident cases of CRC reported to the SEER registries during the entire period (1975-2013). Overall incidence was 75.5/100,000 white persons and 83.6/100,000 black persons. CRC incidence peaked during 1980 through 1989 and began to decrease in 1990. In whites and blacks, the decreases in incidence between the time periods of 1980-1984 and 2010-2013 were limited to the screening-age population (ages 50 years or older). Between these time periods, there was 40% decrease in incidence among whites compared with 26% decrease in incidence among blacks. Decreases in incidence were greater for cancers of the distal colon and rectum, and reductions in these cancers were greater among whites than blacks. CRC incidence among persons younger than 50 years decreased slightly between 1975-1979 and 1990. However, among persons 20-49 years old, CRC incidence increased from 8.3/100,000 persons in 1990-1994 to 11.4/100,000 persons in 2010-2013; incidence rates in younger adults were similar for whites and blacks. CONCLUSIONS: On the basis of an analysis of the SEER cancer registries from 1975 through 2013, CRC incidence decreased only among individuals 50 years or older between the time periods of 1980-1984 and 2010-2013. Incidence increased modestly among individuals 20-49 years old between the time periods of 1990-1994 and 2010-2013. The decision of whether to recommend screening for younger populations requires a formal analysis of risks and benefits. Our observed trends provide compelling evidence that screening has had an important role in reducing CRC incidence

The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission

1Infection of red blood cells (RBC) subjects the malaria parasite to oxidative stress. Therefore, efficient antioxidant and redox systems are required to prevent damage by reactive oxygen species. Plasmodium spp. have thioredoxin and glutathione (GSH) systems that are thought to play a major role as antioxidants during blood stage infection. In this report, we analyzed a critical component of the GSH biosynthesis pathway using reverse genetics. Plasmodium berghei parasites lacking expression of gamma-glutamylcysteine synthetase (γ-GCS), the rate limiting enzyme in de novo synthesis of GSH, were generated through targeted gene disruption thus demonstrating, quite unexpectedly, that γ-GCS is not essential for blood stage development. Despite a significant reduction in GSH levels, blood stage forms of pbggcs− parasites showed only a defect in growth as compared to wild type. In contrast, a dramatic effect on development of the parasites in the mosquito was observed. Infection of mosquitoes with pbggcs− parasites resulted in reduced numbers of stunted oocysts that did not produce sporozoites. These results have important implications for the design of drugs aiming at interfering with the GSH redox-system in blood stages and demonstrate that de novo synthesis of GSH is pivotal for development of Plasmodium in the mosquito

Route knowledge and configural knowledge in typical and atypical development: a comparison of sparse and rich environments

Background: Individuals with Down syndrome (DS) and individuals with Williams syndrome (WS) have poor navigation skills, which impact their potential to become independent. Two aspects of navigation were investigated in these groups, using virtual environments (VE): route knowledge (the ability to learn the way from A to B by following a fixed sequence of turns) and configural knowledge (knowledge of the spatial relationships between places within an environment). Methods: Typically developing (TD) children aged 5 to 11 years (N = 93), individuals with DS (N = 29) and individuals with WS (N = 20) were presented with a sparse and a rich VE grid maze. Within each maze, participants were asked to learn a route from A to B and a route from A to C before being asked to find a novel shortcut from B to C. Results: Performance was broadly similar across sparse and rich mazes. The majority of participants were able to learn novel routes, with poorest performance in the DS group, but the ability to find a shortcut, our measure of configural knowledge, was limited for all three groups. That is, 59 % TD participants successfully found a shortcut, compared to 10 % participants with DS and 35 % participants with WS. Differences in the underlying mechanisms associated with route knowledge and configural knowledge and in the developmental trajectories of performance across groups were observed. Only the TD participants walked a shorter distance in the last shortcut trial compared to the first, indicative of increased configural knowledge across trials. The DS group often used an alternative strategy to get from B to C, summing the two taught routes together. Conclusions: Our findings demonstrate impaired configural knowledge in DS and in WS, with the strongest deficit in DS. This suggests that these groups rely on a rigid route knowledge based method for navigating and as a result are likely to get lost easily. Route knowledge was also impaired in both DS and WS groups and was related to different underlying processes across all three groups. These are discussed with reference to limitations in attention and/or visuo-spatial processing in the atypical groups

Translation Levels Control Multi-Spanning Membrane Protein Expression

Attempts to express eukaryotic multi-spanning membrane proteins at high-levels have been generally unsuccessful. In order to investigate the cause of this limitation and gain insight into the rate limiting processes involved, we have analyzed the effect of translation levels on the expression of several human membrane proteins in Escherichia coli (E. coli). These results demonstrate that excessive translation initiation rates of membrane proteins cause a block in protein synthesis and ultimately prevent the high-level accumulation of these proteins. Moderate translation rates allow coupling of peptide synthesis and membrane targeting, resulting in a significant increase in protein expression and accumulation over time. The current study evaluates four membrane proteins, CD20 (4-transmembrane (TM) helixes), the G-protein coupled receptors (GPCRs, 7-TMs) RA1c and EG-VEGFR1, and Patched 1 (12-TMs), and demonstrates the critical role of translation initiation rates in the targeting, insertion and folding of integral membrane proteins in the E. coli membrane

Downscaling Climate Change Impacts, Socio-Economic Implications and Alternative Adaptation Pathways for Islands and Outermost Regions

This book provides a comprehensive overview of the future scenarios of climate change and management concerns associated with climate change impacts on the blue economy of European islands and outermost regions. The publication collects major findings of the SOCLIMPACT project’s research outcomes, aiming to raise social awareness among policy-makers and industry about climate change consequences at local level, and provide knowledge-based information to support policy design, from local to national level. This comprehensive book will also assist students, scholars and practitioners to understand, conceptualize and effectively and responsibly manage climate change information and applied research. This book provides invaluable material for Blue Growth Management, theory and application, at all levels. This first edition includes up-to-date data, statistics, references, case material and figures of the 12 islands case studies. ¨Downscaling climate change impacts, socio-economic implications and alternative adaptation pathways for Islands and Outermost Regions¨ is a must-read book, given the accessible style and breadth and depth with which the topic is dealt. The book is an up-to-date synthesis of key knowledge on this area, written by a multidisciplinary group of experts on climate and economic modelling, and policy design

Neuropeptidomic Components Generated by Proteomic Functions in Secretory Vesicles for Cell–Cell Communication

Diverse neuropeptides participate in cell–cell communication to coordinate neuronal and endocrine regulation of physiological processes in health and disease. Neuropeptides are short peptides ranging in length from ~3 to 40 amino acid residues that are involved in biological functions of pain, stress, obesity, hypertension, mental disorders, cancer, and numerous health conditions. The unique neuropeptide sequences define their specific biological actions. Significantly, this review article discusses how the neuropeptide field is at the crest of expanding knowledge gained from mass-spectrometry-based neuropeptidomic studies, combined with proteomic analyses for understanding the biosynthesis of neuropeptidomes. The ongoing expansion in neuropeptide diversity lies in the unbiased and global mass-spectrometry-based approaches for identification and quantitation of peptides. Current mass spectrometry technology allows definition of neuropeptide amino acid sequence structures, profiling of multiple neuropeptides in normal and disease conditions, and quantitative peptide measures in biomarker applications to monitor therapeutic drug efficacies. Complementary proteomic studies of neuropeptide secretory vesicles provide valuable insight into the protein processes utilized for neuropeptide production, storage, and secretion. Furthermore, ongoing research in developing new computational tools will facilitate advancements in mass-spectrometry-based identification of small peptides. Knowledge of the entire repertoire of neuropeptides that regulate physiological systems will provide novel insight into regulatory mechanisms in health, disease, and therapeutics

Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone

The hypocretin (orexin) system is involved in sleep/wake regulation, and antagonists of both hypocretin receptor type 1 (HCRTR1) and/or HCRTR2 are considered to be potential hypnotic medications. It is currently unclear whether blockade of either or both receptors is more effective for promoting sleep with minimal side effects. Accordingly, we compared the properties of selective HCRTR1 (SB-408124 and SB-334867) and HCRTR2 (EMPA) antagonists with that of the dual HCRTR1/R2 antagonist almorexant in the rat. All 4 antagonists bound to their respective receptors with high affinity and selectivity in vitro. Since in vivo pharmacokinetic experiments revealed poor brain penetration for SB-408124, SB-334867 was selected for subsequent in vivo studies. When injected in the mid-active phase, SB-334867 produced small increases in rapid-eye-movement (REM) and non-REM (NR) sleep. EMPA produced a significant increase in NR only at the highest dose studied. In contrast, almorexant decreased NR latency and increased both NR and REM proportionally throughout the subsequent 6 h without rebound wakefulness. The increased NR was due to a greater number of NR bouts; NR bout duration was unchanged. At the highest dose tested (100 mg/kg), almorexant fragmented sleep architecture by increasing the number of waking and REM bouts. No evidence of cataplexy was observed. HCRTR1 occupancy by almorexant declined 4–6 h post-administration while HCRTR2 occupancy was still elevated after 12 h, revealing a complex relationship between occupancy of HCRT receptors and sleep promotion. We conclude that dual HCRTR1/R2 blockade is more effective in promoting sleep than blockade of either HCRTR alone. In contrast to GABA receptor agonists which induce sleep by generalized inhibition, HCRTR antagonists seem to facilitate sleep by reducing waking “drive”

Water vapor toward starless cores: the Herschel view

SWAS and Odin provided stringent upper limits on the gas phase water abundance of dark clouds (x(H2O) < 7x10^-9). We investigate the chemistry of water vapor in starless cores beyond the previous upper limits using the highly improved angular resolution and sensitivity of Herschel and measure the abundance of water vapor during evolutionary stages just preceding star formation. High spectral resolution observations of the fundamental ortho water (o-H2O) transition (557 GHz) were carried out with Herschel HIFI toward two starless cores: B68, a Bok globule, and L1544, a prestellar core embedded in the Taurus molecular cloud complex. The rms in the brightness temperature measured for the B68 and L1544 spectra is 2.0 and 2.2 mK, respectively, in a velocity bin of 0.59 km s^-1. The continuum level is 3.5+/-0.2 mK in B68 and 11.4+/-0.4 mK in L1544. No significant feature is detected in B68 and the 3 sigma upper limit is consistent with a column density of o-H2O N(o-H2O) < 2.5x10^13 cm^-2, or a fractional abundance x(o-H2O) < 1.3x10^-9, more than an order of magnitude lower than the SWAS upper limit on this source. The L1544 spectrum shows an absorption feature at a 5 sigma level from which we obtain the first value of the o-H2O column density ever measured in dark clouds: N(o-H2O) = (8+/-4)x10^12 cm^-2. The corresponding fractional abundance is x(o-H2O) ~ 5x10^-9 at radii > 7000 AU and ~2x10^-10 toward the center. The radiative transfer analysis shows that this is consistent with a x(o-H2O) profile peaking at ~10^-8, 0.1 pc away from the core center, where both freeze-out and photodissociation are negligible. Herschel has provided the first measurement of water vapor in dark regions. Prestellar cores such as L1544 (with their high central densities, strong continuum, and large envelopes) are very promising tools to finally shed light on the solid/vapor balance of water in molecular clouds.Comment: Accepted for publication in Astronomy and Astrophysics (HIFI first results issue