The gut fermentation product butyrate displays anti-cancer properties in the human proximal colon, including the ability to inhibit proliferation and induce apoptosis in colorectal cancer (CRC) ...cells. A natural histone deacetylase inhibitor (HDACi), butyrate can alter histone acetylation patterns in CRC cells, and thereby regulate global gene expression, including the non-coding transcriptome and microRNAs (miRNAs). Dysregulated miRNA expression affects CRC development and progression; however, the interplay between miRNA activity and butyrate response remains to be elucidated. A high-throughput functional screen was employed to identify miRNAs that can act as enhancers of the anti-cancer properties of butyrate. Validation studies confirmed that several miRNAs, including miR-125b, miR-181a, miR-593, and miR-1227, enhanced apoptosis, decreased proliferation, and promoted cell-cycle arrest in the presence of butyrate. Pathway analyses of predicted miRNA target genes highlighted their likely involvement in critical cancer-related growth pathways, including WNT and PI3K signaling. Several cancer-associated miRNA targets, including TRIM29, COX2, PIK3R3, CCND1, MET, EEF2K, DVL3, and NUP62 were synergistically regulated by the combination of cognate miRNAs and butyrate. Overall, this study has exposed the potential of miRNAs to act as enhancers of the anti-cancer effects of HDAC inhibition and identifies specific miRNAs that might be exploited for therapeutic benefit.
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Using a functional genomics approach, this study identifies microRNAs that combine with butyrate to slow colon cancer progression. It highlights microRNAs with therapeutic potential and other drug targets whose inhibition may be useful either as a monotherapy or in conjunction with chromatin-modifying drugs.
The reason the InGaN/GaN quantum well system emits intense light even though the dislocation density is high is assessed. First, the evidence from electron microscopy for nanometre-scale In-rich ...clusters in InGaN quantum wells is presented. Such clusters would localize the excitons away from the dislocations and hence the dislocations would not quench the light emission, consistent with observations. However, it is then shown that InGaN damages extremely rapidly under an electron beam, and that the damage causes In-rich clusters to form. No evidence is found of gross indium clustering at low beam currents and short exposure times in the electron microscope. However, at such low electron doses the image is noisy, and low-level indium clustering in InGaN quantum wells could possibly exist, but be masked by the noise. A different technique, 3-dimensional atom probe field ion microscopy, has therefore been used to image the InGaN quantum wells. This reveals that InGaN is a random alloy, with the local statistical fluctuations in indium content expected in a random alloy, but with no indium clustering. Since In-rich clusters are clearly not necessary for bright light emission from InGaN quantum wells, another mechanism must be responsible for the exciton localization observed. It is shown that thickness fluctuations in the InGaN quantum wells of only one monolayer, observed in electron microscopy, result in an exciton confinement energy of 58 meV, sufficient to localize the carriers at room temperature. An alternative localization mechanism due to randomly formed In-N-In chains proposed by others is discussed. It is concluded that In-rich clusters in InGaN quantum wells do not exist in the specimens we have studied, and in any case they are not necessary to localize the excitons and for bright light emission.
P-glycoprotein (Pgp) affects the absorption, distribution, and clearance of a variety of compounds. Thus, identification of compounds that are Pgp substrates can aid drug candidate selection and ...optimization. Our goal was to evaluate three assays used to determine whether compounds are Pgp substrates. Sixty-six compounds were tested in monolayer efflux, ATPase, and calcein-AM assays. Assay results yielded two categories of compounds. Category I (n = 35) exhibited concordance across the assays. Category II (n = 31) revealed differences among the assays that related to the apparent permeability (P(app)) of the compounds. Within category II, two groups were discerned based on the absence (group IIA, n = 10, nontransported substrates) or presence (group IIB, n = 21, transported substrates) of monolayer efflux. Detection of efflux (group IIB) was associated with compounds having low/moderate P(app) values (mean = 16.6 nm/s), whereas inability to detect efflux (group IIA) was associated with compounds having high P(app) values (mean = 535 nm/s). The calcein-AM and ATPase assays revealed Pgp interactions for highly permeable group IIA compounds but were less responsive than monolayer efflux for low/moderate P(app) compounds of group IIB. All assays detected substrates across a broad range of P(app), but the efflux assay was more prone to fail at high P(app), whereas the calcein-AM and ATPase assays were more prone to fail at low P(app). When P(app) is low, efflux is a greater factor in the disposition of Pgp substrates. The efflux assay is more reliable at low/moderate P(app) and is the method of choice for evaluating drug candidates despite low throughput and reliance on liquid chromatography with tandem mass spectrometry.
•We measure mole and gravel mole drain performance in a clay-loam soil.•We examine surface runoff and subsurface drain discharge over 12 rainfall events.•Response times were particularly reactive to ...changes in soil moisture status.•Gravel mole drainage reacted faster to input precipitation than other treatments.•Gravel mole drainage performed better than mole drainage in this soil type.
Shallow drainage techniques such as mole and gravel mole drainage are used in low permeability soils to siphon off infiltrating rainwater and mitigate the associated rise in watertable. Their purpose is to improve trafficability and agricultural production. In Ireland, long-term climate predictions envisage an increased level of short-term extreme rainfall events. Therefore, a key question is how these drainage techniques perform during episodic, high intensity rainfall events, specifically in terms of discharge hydrographs and associated parameters (principally flow start time, flow peak time, lag time, peak flow rate and flashiness index). We examined 12 rainfall events over a 1year period on a clay-loam dominated grassland site of 1.4% slope in the south of Ireland. Four drainage treatments, namely; (A) an un-drained control, (B) Mole drainage installed in January 2011 (sub-optimal installation conditions), (C) Mole drainage installed in July 2011 (optimal installation conditions) and (D) Gravel mole drainage installed in July 2011 were examined. Results showed that gravel mole drainage exhibited shorter response times to rainfall events and ultimately drained greater volumes. Drain flow from mole drainage treatments B and C produced longer start, peak and lag times and lower peak and total flows relative to the other flow discharges. Variations in discharges from all treatments were closely correlated to soil moisture status, 30days antecedent rainfall and rainfall event intensity. Drain flow response in all treatments was seen to deteriorate in time with the strongest responses evident in early events. Flow hydrographs showed strong variation in flow characteristics, within and across treatments and across events. If the predicted increase in short-term extreme rainfall events materialises then such systems will have to operate in increasingly adverse conditions. This will require changes in system design to improve the effectiveness of mole and gravel mole drainage.
There is little empirical evidence to indicate that dairy cow live weight affects the extent of soil damage at the hoof-soil interface during grazing on poorly drained permanent grassland. In the ...present study the impact of Holstein-Friesian (HF) dairy cows with a mean (±standard deviation) live weight of 570 (±61) kg were compared with Jersey × Holstein-Friesian (JX) with a mean live weight of 499 (±52) kg each at two stocking densities: mean 2·42 ± (0·062) and 2·66 (±0·079) cows/ha. Soil physical properties (bulk density, macroporosity, gravimetric water content, air-filled porosity, penetration resistance and shear strength), poaching damage (post-grazing soil surface deformation and hoof-print depth), herbage yield and milk production were measured throughout 2011 and 2012. Soil physical properties, post-grazing soil surface deformation and herbage production were not affected by dairy cow breed or by interactions between breed and stocking density. Hoof-print depth was higher in the HF treatments (39 v. 37 mm, s.e. 0·5 mm). Loading pressure imposed at the soil surface was the same for both breeds due to a direct correlation between live weight and hoof size. Poaching damage was greater at higher stocking density. Using the lighter JX cow offered little advantage in terms of lowering the negative impact of treading on soil physical properties or reducing poaching damage and no advantage in terms of herbage or milk production compared with the heavier HF cow.
The objective of this systems-scale study was to investigate grazing season timeframes on pasture and milk production and on milk processability of dairy systems with compact spring-calving dairy ...cows grazing white clover (Trifolium repens L.) based grassland. Fifty-four primiparous and multiparous Holstein-Friesian dairy cows were used in a one-factor study with 3 systems (n = 18) and repeated over 2 yr (2008/09 and 2009/10). The 3 systems were: early spring calving with annual fertilizer N input of 100 kg·ha−1 applied in spring (ES100N; 2.1 cows·ha−1; grazing February to November), early spring calving without fertilizer N (ES0N; 1.6 cows·ha−1; grazing February to November) and late spring calving without fertilizer N (LS0N; 1.53 cows·ha−1; grazing April to January). Annual pasture production was affected by an interaction between grazing system and year: Mean annual pasture yields for 2008 and 2009 were ES100N; 10.35 and 9.88, ES0N; 8.88 and 8.63, LS0N; 9.18 and 10.31 t of dry matter (DM)·ha−1 (SEM 0.39). LS0N had higher pasture DM yield in 2009 due to higher clover DM production and biological N fixation compared with the other systems. Clover stolon and root mass in the following February was correlated with stolon and root mass in the previous November with 64% of stolon mass present on LS0N in February (R2 = 0.84). There were no detectable differences in per-lactation milk yield (6,335 kg·cow−1), fat, protein and lactose yields (271, 226, 297 kg·cow−1, respectively), cow liveweight (585 kg) or body condition score (3.02). Although winter grazing favored subsequent clover DM production, biological N fixation and pasture DM production, delaying calving date in spring and extending lactation into the following winter led to inefficient use of this pasture by the grazing herd and lowered the quality of late-lactation milk for processing purposes. Hence, a mean calving date in mid- to late-February is recommended for zero-fertilizer N input clover-based grassland.
Little consideration has been given to how farm management, specifically tactics used to implement the management strategy, may influence the carbon footprint (CF) and land use for milk produced on ...commercial farms. In this study, the CF and land use of milk production from 18 Irish commercial dairy farms were analyzed based on foreground data from a 12-mo survey capturing management tactics and background data from the literature. Large variation was found in farm attributes and management tactics; for example, up to a 1.5-fold difference in fertilizer nitrogen input was used to support the same stocking density, and up to a 3.5-fold difference in concentrate fed for similar milk output per cow. However, the coefficient of variation for milk CF between farms only varied by 13% and for land use by 18%. The overall CF and overall land use of the milk production from the 18 dairy farms was 1.23±0.04kg of CO2 Eq and 1.22±0.05 m2 per kilogram of energy-corrected milk. Milk output per cow, economic allocation between exports of milk and liveweight, and on-farm diesel use per ha were found to be influential factors on milk CF, whereas the fertilizer N rate, milk output per cow, and economic allocation between exports of milk and liveweight were influential on land use. Effective sward management of white clover within a few farms appeared to lower the CF but increased on-farm land use. It was concluded that a combination of multiple tactics determines CF and land use for milk production on commercial dairy farms and, although these 2 measures of environmental impact are correlated, a farm with a low CF did not always have low land use and vice versa.
Two solar cells based on an InGaN/GaN p–i–n hetero-junction, but having different dislocation densities, were fabricated and characterized. The structures were grown on c-plane (0001) GaN-on-sapphire ...templates with different threading dislocation (TD) densities of 5×108 and 5×109cm−2. Structural characterization revealed the presence of V-defects in the InGaN epilayer. Since each V-defect was associated with a TD, the structural as well as the optical properties worsened with a higher TD density in the GaN/sapphire template. It was also found that additional dislocations were generated in the p-GaN layer over the V-defects in the InGaN layer. Because of its superior structural quality, the peak external quantum efficiency (EQE) of the low TD density sample was three times higher than that of the high TD density sample.
•Two InGaN/GaN solar cells containing different threading dislocation (TD) densities were fabricated and characterized.•The peak EQE of the cell with a low TD density (5×108cm−2) is three times higher than that with a high TD density (5×109cm−2).•The two cells show similar short-circuit current (Isc), open-circuit voltage (Voc) and fill factor.•(S)TEM characterization reveals V-pits associated with TDs in the InGaN absorption layer which deteriorates the efficiency of the cells.
Aberration-corrected scanning transmission electron microscopy was used to investigate the core structures of threading dislocations in undoped GaN films with both high and low dislocation densities, ...and in a comparable high dislocation density Mg-doped GaN film. All a-type dislocations in all samples have a 5/7-atom core structure. In contrast, most (a+c)-type dislocations in undoped GaN dissociate due to local strain variations from nearby dislocations. In contrast, Mg doping prevents (a+c)-type dislocation dissociation. Our data indicate that Mg affects dislocation cores in GaN significantly.
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