Highlights • The small molecule inhibitor of the inflammasome, MC950, attenuates Aβ+LPS-induced inflammasome activation in microglia. • It increases phagocytosis of Aβ by microglia in vitro. • Oral ...administration of MC950, reduces Aβ accumulation in APP/PS1 mice. • This is accompanied by improved cognitive function and decreased neuroinflammation.
New laboratory and animal sampling methods and data have been generated over the last 10 yr that had the potential to improve the predictions for energy, protein, and AA supply and requirements in ...the Cornell Net Carbohydrate and Protein System (CNCPS). The objectives of this study were to describe updates to the CNCPS and evaluate model performance against both literature and on-farm data. The changes to the feed library were significant and are reported in a separate manuscript. Degradation rates of protein and carbohydrate fractions were adjusted according to new fractionation schemes, and corresponding changes to equations used to calculate rumen outflows and postrumen digestion were presented. In response to the feed-library changes and an increased supply of essential AA because of updated contents of AA, a combined efficiency of use was adopted in place of separate calculations for maintenance and lactation to better represent the biology of the cow. Four different data sets were developed to evaluate Lys and Met requirements, rumen N balance, and milk yield predictions. In total 99 peer-reviewed studies with 389 treatments and 15 regional farms with 50 different diets were included. The broken-line model with plateau was used to identify the concentration of Lys and Met that maximizes milk protein yield and content. Results suggested concentrations of 7.00 and 2.60% of metabolizable protein (MP) for Lys and Met, respectively, for maximal protein yield and 6.77 and 2.85% of MP for Lys and Met, respectively, for maximal protein content. Updated AA concentrations were numerically higher for Lys and 11 to 18% higher for Met compared with CNCPS v6.0, and this is attributed to the increased content of Met and Lys in feeds that were previously incorrectly analyzed and described. The prediction of postruminal flows of N and milk yield were evaluated using the correlation coefficient from the BLUP (R2BLUP) procedure or model predictions (R2MDP) and the concordance correlation coefficient. The accuracy and precision of rumen-degradable N and undegradable N and bacterial N flows were improved with reduced bias. The CNCPS v6.5 predicted accurate and precise milk yield according to the first-limiting nutrient (MP or metabolizable energy) with a R2BLUP=0.97, R2MDP=0.78, and concordance correlation coefficient=0.83. Furthermore, MP-allowable milk was predicted with greater precision than metabolizable energy–allowable milk (R2MDP=0.82 and 0.76, respectively, for MP and metabolizable energy). Results suggest a significant improvement of the model, especially under conditions of MP limitation.
Hydrothermal impacts on trace element and isotope ocean biogeochemistry German, C. R.; Casciotti, K. A.; Dutay, J.-C. ...
Philosophical transactions - Royal Society. Mathematical, Physical and engineering sciences/Philosophical transactions - Royal Society. Mathematical, physical and engineering sciences,
11/2016, Letnik:
374, Številka:
2081
Journal Article
Recenzirano
Odprti dostop
Hydrothermal activity occurs in all ocean basins, releasing high concentrations of key trace elements and isotopes (TEIs) into the oceans. Importantly, the calculated rate of entrainment of the ...entire ocean volume through turbulently mixing buoyant hydrothermal plumes is so vigorous as to be comparable to that of deep-ocean thermohaline circulation. Consequently, biogeochemical processes active within deep-ocean hydrothermal plumes have long been known to have the potential to impact global-scale biogeochemical cycles. More recently, new results from GEOTRACES have revealed that plumes rich in dissolved Fe, an important micronutrient that is limiting to productivity in some areas, are widespread above mid-ocean ridges and extend out into the deep-ocean interior. While Fe is only one element among the full suite of TEIs of interest to GEOTRACES, these preliminary results are important because they illustrate how inputs from seafloor venting might impact the global biogeochemical budgets of many other TEIs. To determine the global impact of seafloor venting, however, requires two key questions to be addressed: (i) What processes are active close to vent sites that regulate the initial high-temperature hydrothermal fluxes for the full suite of TEIs that are dispersed through non-buoyant hydrothermal plumes? (ii) How do those processes vary, globally, in response to changing geologic settings at the seafloor and/or the geochemistry of the overlying ocean water? In this paper, we review key findings from recent work in this realm, highlight a series of key hypotheses arising from that research and propose a series of new GEOTRACES modelling, section and process studies that could be implemented, nationally and internationally, to address these issues.
This article is part of the themed issue ‘Biological and climatic impacts of ocean trace element chemistry’.
ABSTRACT
Age‐related macular degeneration (AMD) is a leading cause of vision loss, characterized by drusen deposits and thickened Bruch's membrane (BM). This study details the capacity of nanosecond ...laser treatment to reduce drusen and thin BM while maintaining retinal structure. Fifty patients with AMD had a single nanosecond laser treatment session and after 2 yr, change in drusen area was compared with an untreated cohort of patients. The retinal effect of the laser was determined in human and mouse eyes using immunohistochemistry and compared with untreated eyes. In a mouse with thickened BM (ApoEnull), the effect of laser treatment was quantified using electron microscopy and quantitative PCR. In patients with AMD, nanosecond laser treatment reduced drusen load at 2 yr. Retinal structure was not compromised in human and mouse retina after laser treatment, with only a discrete retinal pigment epithelium (RPE) injury, and limited mononuclear cell response observed. BM was thinned in the ApoEnull mouse 3 mo after treatment (ApoEnull treated 683 ± 38 ran, ApoEnull untreated 890 ± 60 nm, C57B16J 606 ± 43 nm), with the expression of matrix metalloproteinase‐2 and ‐3 increased (>260%). Nanosecond laser resolved drusen independent of retinal damage and improved BM structure, suggesting this treatment has the potential to reduce AMD progression.—Jobling, A. I., Guymer, R. H., Vessey, K. A., Greferath, U., Mills, S. A., Brassington, K. H., Luu, C. D., Aung, K. Z., Trogrlic, L., Plunkett, M., Fletcher, E. L. Nanosecond laser therapy reverses pathologic and molecular changes in age‐related macular degeneration without retinal damage. FASEB J. 29, 696‐710 (2015). www.fasebj.org
Dreissenid mussels (the zebra mussel Dreissena polymorpha and the quagga mussel D. bugensis) are ecosystem engineers that modify the physical environment by increasing light penetration. Such a ...change is likely to affect the distribution and diversity of submerged macrophytes. Filter-feeding by these mussels has been associated with increased water clarity in many North American and European lakes. In this study, we report the increase in water clarity of Oneida Lake, New York, USA, for 1975-2002 and argue that the increase was caused by zebra mussel invasion rather than declines in nutrients. Over the study period, although mean total phosphorus decreased significantly, the main increase in water clarity occurred after the zebra mussel invasion in 1991. The average depth receiving 1% surface light increased from 6.7 m to 7.8 m after the invasion of zebra mussels, representing a 23% areal expansion. The maximum depth of macrophyte colonization, as measured by diver and hydroacoustic surveys, increased from 3.0 m before the invasion of zebra mussels to 5.1 m after their establishment. In addition, macrophyte species richness increased, the frequency of occurrence increased for most species, and the composition of the macrophyte community changed from low-light-tolerant species to those tolerating a wide range of light conditions. Comparisons with observations reported in the literature indicate that increased light penetration alone could explain these changes in macrophyte distribution and diversity. Such changes will increase the importance of benthic primary production over pelagic production in the food web, thereby representing an overall alteration of ecosystem function, a process we refer to as “benthification”.
We examined stressors that have led to profound ecological changes in the Lake Ontario ecosystem and its fish community since 1970. The most notable changes have been reductions in phosphorus ...loading, invasion by Dreissena spp., fisheries management through stocking of exotic salmonids and control of sea lamprey (Petromyzon marinus), and fish harvest by anglers and double-crested cormorants (Phalacrocorax auritus). The response to these stressors has led to (i) declines in both algal photosynthesis and epilimnetic zooplankton production, (ii) decreases in alewife (Alosa pseudoharengus) abundance, (iii) declines in native Diporeia and lake whitefish (Coregonus clupeaformis), (iv) behavioral shifts in alewife spatial distribution benefitting native lake trout (Salvelinus namaycush), threespine stickleback (Gasterosteus aculeatus), and emerald shiner (Notropis atherinoides) populations, (v) dramatic increases in water clarity, (vi) predation impacts by cormorants on select fish species, and (vii) lake trout recruitment bottlenecks associated with alewife-induced thiamine deficiency. We expect stressor responses associated with anthropogenic forces like exotic species invasions and global climate warming to continue to impact the Lake Ontario ecosystem in the future and recommend continuous long-term ecological studies to enhance scientific understanding and management of this important resource.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We report the first measurement of the double-differential and total muon neutrino charged current inclusive cross sections on argon at a mean neutrino energy of 0.8 GeV. Data were collected using ...the MicroBooNE liquid argon time projection chamber located in the Fermilab Booster neutrino beam and correspond to 1.6×1020 protons on target of exposure. The measured differential cross sections are presented as a function of muon momentum, using multiple Coulomb scattering as a momentum measurement technique, and the muon angle with respect to the beam direction. We compare the measured cross sections to multiple neutrino event generators and find better agreement with those containing more complete treatment of quasielastic scattering processes at low Q2. The total flux integrated cross section is measured to be 0.693±0.010(stat)±0.165(syst)×10−38 cm2.
•Identified epitope-mimicking sequences were in general conformational.•Each patient had a distinct IgE as well as IgG4 epitope recognition profile.•In general the IgG4 epitope pattern was more ...heterogeneous than the IgE pattern.•The phage-display technology was useful for studying antibody epitope patterns.
Development and maintenance of tolerance to food allergens appears to be associated with alterations in antigen specific IgE and IgG4 responses. Previous studies have focused only on comparing IgE and IgG4 linear epitope recognition patterns but take no account of conformational epitopes.
The aim of this study was to compare Ara h 1-specific IgE and IgG4 epitope recognition patterns in patients with severe peanut allergy, applying a method allowing for identification of both linear and conformational epitopes.
Polyclonal sera from three individual patients, suffering from severe allergic reaction to peanuts, including anaphylaxis, were used to analyse the IgE and IgG4 epitope recognition patterns of the major peanut allergen Ara h 1. Epitope identification was conducted by competitive immuno-screening of a phage-displayed random heptamer peptide library. Resulting epitope-mimicking sequences were aligned for identification of consensus sequences and localised on the surface of the Ara h 1 molecule by a computer-based algorithm.
All epitope-mimicking sequences identified were found to correspond to conformational epitopes. Each individual patient had his/her own distinct IgE as well as IgG4 epitope recognition profile, though some important IgE epitopes were common to all patients. In general the IgG4 epitope pattern was more heterogeneous than the IgE pattern, did not coincide with IgE epitopes and had a lower affinity than IgE.
This study demonstrated the usefulness of the phage-display technology in distinguishing between the epitope pattern of IgE and IgG4, giving detailed information on fine specificity and affinity. Competitive immuno-screening of phage-display random peptide libraries could be a future valuable tool to study the balance and dynamics of the IgE and IgG4 epitope recognition repertoire and provide a diagnostic tool giving information on the associated allergic phenotype.
c-Met represents an important emerging therapeutic target in cancer. In this study, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive ...Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation, resulting in marked inhibition of NPC cell growth and invasion. Strikingly, inhibition of c-Met resulted in significant downregulation of TP53-induced Glycolysis and Apoptosis Regulator (TIGAR) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in the growth inhibitory activity of c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings reveal a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provide the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers.
The first concerted multi-model intercomparison of halogenated very short-lived substances (VSLS) has been performed, within the framework of the ongoing Atmospheric Tracer Transport Model ...Intercomparison Project (TransCom). Eleven global models or model variants participated (nine chemical transport models and two chemistry–climate models) by simulating the major natural bromine VSLS, bromoform (CHBr3) and dibromomethane (CH2Br2), over a 20-year period (1993–2012). Except for three model simulations, all others were driven offline by (or nudged to) reanalysed meteorology. The overarching goal of TransCom-VSLS was to provide a reconciled model estimate of the stratospheric source gas injection (SGI) of bromine from these gases, to constrain the current measurement-derived range, and to investigate inter-model differences due to emissions and transport processes. Models ran with standardised idealised chemistry, to isolate differences due to transport, and we investigated the sensitivity of results to a range of VSLS emission inventories. Models were tested in their ability to reproduce the observed seasonal and spatial distribution of VSLS at the surface, using measurements from NOAA's long-term global monitoring network, and in the tropical troposphere, using recent aircraft measurements – including high-altitude observations from the NASA Global Hawk platform. The models generally capture the observed seasonal cycle of surface CHBr3 and CH2Br2 well, with a strong model–measurement correlation (r ≥ 0.7) at most sites. In a given model, the absolute model–measurement agreement at the surface is highly sensitive to the choice of emissions. Large inter-model differences are apparent when using the same emission inventory, highlighting the challenges faced in evaluating such inventories at the global scale. Across the ensemble, most consistency is found within the tropics where most of the models (8 out of 11) achieve best agreement to surface CHBr3 observations using the lowest of the three CHBr3 emission inventories tested (similarly, 8 out of 11 models for CH2Br2). In general, the models reproduce observations of CHBr3 and CH2Br2 obtained in the tropical tropopause layer (TTL) at various locations throughout the Pacific well. Zonal variability in VSLS loading in the TTL is generally consistent among models, with CHBr3 (and to a lesser extent CH2Br2) most elevated over the tropical western Pacific during boreal winter. The models also indicate the Asian monsoon during boreal summer to be an important pathway for VSLS reaching the stratosphere, though the strength of this signal varies considerably among models. We derive an ensemble climatological mean estimate of the stratospheric bromine SGI from CHBr3 and CH2Br2 of 2.0 (1.2–2.5) ppt, ∼ 57 % larger than the best estimate from the most recent World Meteorological Organization (WMO) Ozone Assessment Report. We find no evidence for a long-term, transport-driven trend in the stratospheric SGI of bromine over the simulation period. The transport-driven interannual variability in the annual mean bromine SGI is of the order of ±5 %, with SGI exhibiting a strong positive correlation with the El Niño–Southern Oscillation (ENSO) in the eastern Pacific. Overall, our results do not show systematic differences between models specific to the choice of reanalysis meteorology, rather clear differences are seen related to differences in the implementation of transport processes in the models.
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