Relating Agulhas leakage to the Agulhas Current retroflection location

The relation between the Agulhas Current retroflection location and the magnitude of Agulhas leakage, the transport of water from the Indian to the Atlantic Ocean, is investigated in a high-resolution numerical ocean model. Sudden eastward retreats of the Agulhas Current retroflection loop are linearly related to the shedding of Agulhas rings, where larger retreats generate larger rings. Using numerical Lagrangian floats a 37 year time series of the magnitude of Agulhas leakage in the model is constructed. The time series exhibits large amounts of variability, both on weekly and annual time scales. A linear relation is found between the magnitude of Agulhas leakage and the location of the Agulhas Current retroflection, both binned to three month averages. In the relation, a more westward location of the Agulhas Current retroflection corresponds to an increased transport from the Indian Ocean to the Atlantic Ocean. When this relation is used in a linear regression and applied to almost 20 years of altimetry data, it yields a best estimate of the mean magnitude of Agulhas leakage of 13.2 Sv. The early retroflection of 2000, when Agulhas leakage was probably halved, can be identified using the regression

Sequential boundaries approach in clinical trials with unequal allocation ratios

BACKGROUND: In clinical trials, both unequal randomization design and sequential analyses have ethical and economic advantages. In the single-stage-design (SSD), however, if the sample size is not adjusted based on unequal randomization, the power of the trial will decrease, whereas with sequential analysis the power will always remain constant. Our aim was to compare sequential boundaries approach with the SSD when the allocation ratio (R) was not equal. METHODS: We evaluated the influence of R, the ratio of the patients in experimental group to the standard group, on the statistical properties of two-sided tests, including the two-sided single triangular test (TT), double triangular test (DTT) and SSD by multiple simulations. The average sample size numbers (ASNs) and power (1-β) were evaluated for all tests. RESULTS: Our simulation study showed that choosing R = 2 instead of R = 1 increases the sample size of SSD by 12% and the ASN of the TT and DTT by the same proportion. Moreover, when R = 2, compared to the adjusted SSD, using the TT or DTT allows to retrieve the well known reductions of ASN observed when R = 1, compared to SSD. In addition, when R = 2, compared to SSD, using the TT and DTT allows to obtain smaller reductions of ASN than when R = 1, but maintains the power of the test to its planned value. CONCLUSION: This study indicates that when the allocation ratio is not equal among the treatment groups, sequential analysis could indeed serve as a compromise between ethicists, economists and statisticians

Oceanography promotes self-recruitment in a planktonic larval disperser

The application of high-resolution genetic data has revealed that oceanographic connectivity in marine species with planktonic larvae can be surprisingly limited, even in the absence of major barriers to dispersal. Australia's southern coast represents a particularly interesting system for studying planktonic larval dispersal, as the hydrodynamic regime of the wide continental shelf has potential to facilitate onshore retention of larvae. We used a seascape genetics approach (the joint analysis of genetic data and oceanographic connectivity simulations) to assess population genetic structure and self-recruitment in a broadcast-spawning marine gastropod that exists as a single meta-population throughout its temperate Australian range. Levels of self-recruitment were surprisingly high, and oceanographic connectivity simulations indicated that this was a result of low-velocity nearshore currents promoting the retention of planktonic larvae in the vicinity of natal sites. Even though the model applied here is comparatively simple and assumes that the dispersal of planktonic larvae is passive, we find that oceanography alone is sufficient to explain the high levels of genetic structure and self-recruitment. Our study contributes to growing evidence that sophisticated larval behaviour is not a prerequisite for larval retention in the nearshore region in planktonic-developing species

Tight junction defects are seen in the buccal mucosa of patients receiving standard dose chemotherapy for cancer

Oral mucositis is one of the most common and debilitating side effects of chemotherapy treatment. Patients are often unable to eat and drink, which can lead to poor clinical outcomes and extensive resource utilisation. The primary aim of this study was to determine the molecular integrity of oral epithelial tight junctions in patients undergoing chemotherapy. The secondary aim was to correlate these changes with proinflammatory cytokines and matrix metalloproteinase profiles.Patients (n = 23) were recruited from the Royal Adelaide Hospital between 2000 and 2003. Reach patient underwent two oral buccal mucosa biopsies (4 mm): one prior to chemotherapy treatment and a second one after chemotherapy treatment. Oral buccal mucosa biopsies were also taken from seven healthy volunteers with no history of cancer, chemo- or radiotherapy treatment or inflammatory disorders. Routine haematoxylin and eosin staining was performed to determine epithelial thickness. Immunohistochemical staining was performed for claudin-1, zonular occludens-1, occludin, interleukin-1β, tumour necrosis factor, interleukin-6, matrix metalloproteinase-2 and metalloproteinase-9.Patients receiving standard dose chemotherapy had significant epithelial atrophy. Elevations in all cytokines and matrix metalloproteinases were seen, with significant lamina propria staining for interleukin-6 and tumour necrosis factor. Matrix metalloproteinase-2 appeared most upregulated within the oral epithelium. These changes coincided with altered tight junction staining properties. Changes in the staining intensity and localisation were both noted, with clear cytoplasmic staining for zonular occludens-1 and claudin-1 in patients treated with chemotherapy.Chemotherapy causes defects in oral tight junctions, coupled with altered cytokine and matrix metalloproteinase profiles. Tight junction disruption in the epithelium may contribute to ulcer development or lead to poor tissue integrity, and the timing of these events may be a target for preventative treatment.Hannah R. Wardill, Richard M. Logan, Joanne M. Bowen, Ysabella Z. A. Van Sebille, Rachel J. Gibso

A novel in vitro platform for the study of SN38-induced mucosal damage and the development of Toll-like receptor 4-targeted therapeutic options

Tight junction and epithelial barrier disruption is a common trait of many gastrointestinal pathologies, including chemotherapy-induced gut toxicity. Currently, there are no validated in vitro models suitable for the study of chemotherapy-induced mucosal damage that allow paralleled functional and structural analyses of tight junction integrity. We therefore aimed to determine if a transparent, polyester membrane insert supports a polarized T84 monolayer with the phenotypically normal tight junctions. T84 cells (passage 5-15) were seeded into either 0.6 cm(2), 0.4 µm pore mixed-cellulose transwell hanging inserts or 1.12 cm(2), 0.4 µm pore polyester transwell inserts at varying densities. Transepithelial electrical resistance was measured daily to assess barrier formation. Immunofluoresence for key tight junction proteins (occludin, zonular occludens-1, claudin-1) and transmission electron microscopy were performed to assess tight junction integrity, organelle distribution, and polarity. Reverse transcription-polymerase chain reaction was performed to determine expression of toll-like receptor 4 (TLR4). Liquid chromatography was also conducted to assess SN38 degradation in this model. Polyester membrane inserts support a polarized T84 phenotype with functional tight junctions in vitro. Transmission electron microscopy indicated polarity, with apico-laterally located tight junctions. Immunofluorescence showed membranous staining for all tight junction proteins. No internalization was evident. T84 cells expressed TLR4, although this was significantly lower than levels seen in HT29 cells (P = .0377). SN38 underwent more rapid degradation in the presence of cells (-76.04 ± 1.86%) compared to blank membrane (-48.39 ± 4.01%), indicating metabolic processes. Polyester membrane inserts provide a novel platform for paralleled functional and structural analysis of tight junction integrity in T84 monolayers. T84 cells exhibit the unique ability to metabolize SN38 as well as expressing TLR4, making this an excellent platform to study clinically relevant therapeutic interventions for SN38-induced mucosal damage by targeting TLR4.Hannah R Wardill, Rachel J Gibson, Ysabella ZA Van Sebille, Kate R Secombe, Richard M Logan, and Joanne M Bowe

TLR4-dependent claudin-1 internalization and secretagogue-mediated chloride secretion regulate irinotecan-induced diarrhea

Published OnlineFirst August 22, 2016Abstract not availableHannah R.Wardill, Joanne M. Bowen, Ysabella Z.A. Van Sebille, Kate R. Secombe, Janet K. Coller, Imogen A. Ball, Richard M. Logan, and Rachel J Gibso

Water mass pathways to the North Atlantic oxygen minimum zone

23 pages, 14 figures, 1 table, supporting information http://dx.doi.org/10.1002/2014JC010557The water mass pathways to the North Atlantic Oxygen Minimum Zone (naOMZ) are traditionally sketched within the cyclonic tropical circulation via the poleward branching from the eastward flowing jets that lie south of 10°N. However, our water mass analysis of historic hydrographic observations together with numerical Lagrangian experiments consistently reveal that the potential density level of σθ = 26.8 kg m-3 (σ26.8, approximately 300 m depth) separates two distinct regimes of circulation within the Central Water (CW) stratum of the naOMZ. In the upper CW (above σ26.8), and in agreement with previous studies, the supply of water mainly comes from the south with a predominant contribution of South Atlantic CW. In the lower CW (below σ26.8), where minimal oxygen content is found, the tropical pathway is instead drastically weakened in favor of a subtropical pathway. More than two thirds of the total water supply to this lower layer takes place north of 10°N, mainly via an eastward flow at 14°N and northern recirculations from the northern subtropical gyre. The existence of these northern jets explains the greater contribution of North Atlantic CW observed in the lower CW, making up to 50% of the water mass at the naOMZ core. The equatorward transfer of mass from the well-ventilated northern subtropical gyre emerges as an essential part of the ventilation of the naOMZ. © 2015. American Geophysical Union. All Rights ReservedThis research has been funded by the Spanish Ministerio de Economía y Competitividad through projects MOC2 (CTM2008–06438-C02-01) and TIC-MOC (CTM2011–28867). J. Peña- Izquierdo has been supported through a FPI predoctoral grant linked to MOC2. E. van Sebille was supported by the Australian Research Council via grant DE130101336 and P. J. Llanillo was partly funded by CONICYT/FONDECYT de Postdoctorado through project 3150229. The authors acknowledge the NODC and Argo Program for making hydrographic data freely available (http://www.nodc.noaa.gov and http://www.coriolis.eu.org). We also thank the ECCO2/NASA program for providing the numerical assimilative simulation via their web page (http://ecco2.jpl.nasa.gov/products/)Peer Reviewe

Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms

Published Online First March 29, 2016Abstract not availableHannah R. Wardill, Rachel J. Gibson, Ysabella Z.A. Van Sebille, Kate R. Secombe, Janet K. Coller, Imogen A. White, Jim Manavis, Mark R. Hutchinson, Vasiliki Staikopoulos, Richard M. Logan, and Joanne M. Bowe

Routine assessment of the gut microbiome to promote preclinical research reproducibility and transparency

Letter. Published online 9 January 2017Hannah R Wardill, Joanne M Bowen, Ysabella ZA Van Sebille, Rachel J Gibso