The evolution of pellet size and shape during spheronisation of an extruded microcrystalline cellulose paste

The process by which cylindrical rods of soft solid paste extrudate are converted into round pellets on a spheroniser (Marumeriser™) plate was studied by interrupting spheronisation tests and measuring the size and shape of the pellets. Batches of 20 identical rods (20 mm long, 3 mm diameter) generated by ram extrusion of 47 wt% microcrystalline cellulose/water paste were spheronised at rotational speeds, ω, between 1200 rpm and 1800 rpm on a laboratory spheroniser. The time to complete spheronisation was found to scale with ω−3.6, which was close to the ω−3dependency predicted by a simple collision model. Breakage occupied the first 10% of the process duration: rounding off was the rate-determining step. The evolution of pellet shape was classified into five stages, the duration of which was found to scale with spheronisation time. Pellet shape, quantified by aspect ratio, circularity, shape and angularity factors presented by Sukumaran and Ashmawy (2001), showed similar behaviour for all ω studied. A phenomenological model is proposed which identifies different routes for small and large rod breakage products.This is the accepted manuscript of an article originally published in Chemical Engineering Research and Design. The final published version is available from Elsevier at http://www.sciencedirect.com/science/article/pii/S0263876214000379

Differential expression of microRNAs in plasma of patients with colorectal cancer: A potential marker for colorectal cancer screening

Objective: MicroRNAs (miRNAs) have been shown to offer great potential in the diagnosis of cancer. We investigated whether plasma miRNAs could discriminate between patients with and without colorectal cancer (CRC). Methods: This study was divided into three phases: (1) marker discovery using real-time PCR-based miRNA profiling on plasma, corresponding cancerous and adjacent non-cancerous colonic tissues of five patients with CRC, along with plasma from five healthy individuals as controls; (2) marker selection and validation by real-time quantitative RT-PCR on a small set of plasma; and (3) independent validation on a large set of plasma from 90 patients with CRC, 20 patients with gastric cancer, 20 patients with inflammatory bowel disease (IBD) and 50 healthy controls. Results: Of the panel of 95 miRNAs analysed, five were upregulated both in plasma and tissue samples. All the five miRNAs were validated on the plasma of 25 patients with CRC and 20 healthy controls. Both miR-17-3p and miR-92 were significantly elevated in the patients with CRC (p<0.0005). The plasma levels of these markers were significantly reduced after surgery in 10 patients with CRC (p<0.05). Further validation with an independent set of plasma samples (n=180) indicated that miR-92 differentiates CRC from gastric cancer, IBD and normal subjects. This marker yielded a receiver operating characteristic curve area of 88.5%. At a cut-off of 240 (relative expression in comparison to RNU6B snRNA), the sensitivity was 89% and the specificity was 70% in discriminating CRC from control subjects. Conclusion: MiR-92 is significantly elevated in plasma of patients with CRC and can be a potential non-invasive molecular marker for CRC screening.published_or_final_versio

The distribution of satellites around massive galaxies at 1<z<3 in ZFOURGE/CANDELS: dependence on star formation activity

We study the statistical distribution of satellites around star-forming and quiescent central galaxies at 1<z<3 using imaging from the FourStar Galaxy Evolution Survey (ZFOURGE) and the Cosmic Assembly Near-IR Deep Extragalactic Legacy Survey (CANDELS). The deep near-IR data select satellites down to $\log(M/M_\odot)>9$ at z<3. The radial satellite distribution around centrals is consistent with a projected NFW profile. Massive quiescent centrals, $\log(M/M_\odot)>10.78$, have $\sim$2 times the number of satellites compared to star-forming centrals with a significance of 2.7$\sigma$ even after accounting for differences in the centrals' stellar-mass distributions. We find no statistical difference in the satellite distributions of intermediate-mass quiescent and star-forming centrals, $10.48<\log(M/M_\odot)<10.78$. Comparing to the Guo2011 semi-analytic model, the excess number of satellites indicates that quiescent centrals have halo masses 0.3 dex larger than star-forming centrals, even when the stellar-mass distributions are fixed. We use a simple toy model that relates halo mass and quenching, which roughly reproduces the observed quenched fractions and the differences in halo mass between star-forming and quenched galaxies only if galaxies have a quenching probability that increases with halo mass from $\sim$0 for $\log(M_h/M_\odot)\sim$11 to $\sim$1 for $\log(M_h/M_\odot)\sim$13.5. A single halo-mass quenching threshold is unable to reproduce the quiescent fraction and satellite distribution of centrals. Therefore, while halo quenching may be an important mechanism, it is unlikely to be the only factor driving quenching. It remains unclear why a high fraction of centrals remain star-forming even in relatively massive halos.Comment: 19 pages, 17 figures, accepted by ApJ. Information on ZFOURGE can be found at http://zfourge.tamu.ed

Does pre-existing morbidity influences risks and benefits of total hip replacement for osteoarthritis: a prospective study of 6682 patients from linked national datasets in England.

Total hip arthroplasty (THA) surgery for elderly people with multimorbidity increases the risk of serious health hazards including mortality. Whether such background morbidity reduces the clinical benefit is less clear. OBJECTIVE: To evaluate how pre-existing health status, using multiple approaches, influences risks of, and quality of life benefits from, THA. SETTING: Longitudinal record linkage study of a UK sample linking their primary care to their secondary care records. PARTICIPANTS: A total of 6682 patients were included, based on the recording of the diagnosis of hip osteoarthritis in a national primary care register and the recording of the receipt of THA in a national secondary care register.Data were extracted from the primary care register on background health and morbidity status using five different constructs: Charlson Comorbidity Index, Electronic Frailty Index (eFI) and counts of comorbidity disorders (from list of 17), prescribed medications and number of primary care visits prior to recording of THA. OUTCOME MEASURES: (1) Postoperative complications and mortality; (2) postoperative hip pain and function using the Oxford Hip Score (OHS) and health-related quality of life using the EuroQoL (EQ)-5D score. RESULTS: Perioperative complication rate was 3.2% and mortality was 0.9%, both increased with worse preoperative health status although this relationship varied depending on the morbidity construct: the eFI showing the strongest relationship but number of visits having no predictive value. By contrast, the benefits were not reduced in those with worse preoperative health, and improvement in both OHS and EQ-5D was observed in all the morbidity categories. CONCLUSIONS: Independent of preoperative morbidity, THA leads to similar substantial improvements in quality of life. These are offset by an increase in medical complications in some subgroups of patients with high morbidity, depending on the definition used. For most elderly people, their other health disorders should not be a barrier for THA

Motion frozen 18F-FDG cardiac PET

BackgroundPET reconstruction incorporating spatially variant 3D Point Spread Function (PSF) improves contrast and image resolution. "Cardiac Motion Frozen" (CMF) processing eliminates the influence of cardiac motion in static summed images. We have evaluated the combined use of CMF- and PSF-based reconstruction for high-resolution cardiac PET.MethodsStatic and 16-bin ECG-gated images of 20 patients referred for (18)F-FDG myocardial viability scans were obtained on a Siemens Biograph-64. CMF was applied to the gated images reconstructed with PSF. Myocardium to blood contrast, maximum left ventricle (LV) counts to defect contrast, contrast-to-noise (CNR) and wall thickness with standard reconstruction (2D-AWOSEM), PSF, ED-gated PSF, and CMF-PSF were compared.ResultsThe measured wall thickness was 18.9 ± 5.2 mm for 2D-AWOSEM, 16.6 ± 4.5 mm for PSF, and 13.8 ± 3.9 mm for CMF-PSF reconstructed images (all P &lt; .05). The CMF-PSF myocardium to blood and maximum LV counts to defect contrasts (5.7 ± 2.7, 10.0 ± 5.7) were higher than for 2D-AWOSEM (3.5 ± 1.4, 6.5 ± 3.1) and for PSF (3.9 ± 1.7, 7.7 ± 3.7) (CMF vs all other, P &lt; .05). The CNR for CMF-PSF (26.3 ± 17.5) was comparable to PSF (29.1 ± 18.3), but higher than for ED-gated dataset (13.7 ± 8.8, P &lt; .05).ConclusionCombined CMF-PSF reconstruction increased myocardium to blood contrast, maximum LV counts to defect contrast and maintained equivalent noise when compared to static summed 2D-AWOSEM and PSF reconstruction

An experimental study of the intrinsic stability of random forest variable importance measures

BACKGROUND: The stability of Variable Importance Measures (VIMs) based on random forest has recently received increased attention. Despite the extensive attention on traditional stability of data perturbations or parameter variations, few studies include influences coming from the intrinsic randomness in generating VIMs, i.e. bagging, randomization and permutation. To address these influences, in this paper we introduce a new concept of intrinsic stability of VIMs, which is defined as the self-consistence among feature rankings in repeated runs of VIMs without data perturbations and parameter variations. Two widely used VIMs, i.e., Mean Decrease Accuracy (MDA) and Mean Decrease Gini (MDG) are comprehensively investigated. The motivation of this study is two-fold. First, we empirically verify the prevalence of intrinsic stability of VIMs over many real-world datasets to highlight that the instability of VIMs does not originate exclusively from data perturbations or parameter variations, but also stems from the intrinsic randomness of VIMs. Second, through Spearman and Pearson tests we comprehensively investigate how different factors influence the intrinsic stability. RESULTS: The experiments are carried out on 19 benchmark datasets with diverse characteristics, including 10 high-dimensional and small-sample gene expression datasets. Experimental results demonstrate the prevalence of intrinsic stability of VIMs. Spearman and Pearson tests on the correlations between intrinsic stability and different factors show that #feature (number of features) and #sample (size of sample) have a coupling effect on the intrinsic stability. The synthetic indictor, #feature/#sample, shows both negative monotonic correlation and negative linear correlation with the intrinsic stability, while OOB accuracy has monotonic correlations with intrinsic stability. This indicates that high-dimensional, small-sample and high complexity datasets may suffer more from intrinsic instability of VIMs. Furthermore, with respect to parameter settings of random forest, a large number of trees is preferred. No significant correlations can be seen between intrinsic stability and other factors. Finally, the magnitude of intrinsic stability is always smaller than that of traditional stability. CONCLUSION: First, the prevalence of intrinsic stability of VIMs demonstrates that the instability of VIMs not only comes from data perturbations or parameter variations, but also stems from the intrinsic randomness of VIMs. This finding gives a better understanding of VIM stability, and may help reduce the instability of VIMs. Second, by investigating the potential factors of intrinsic stability, users would be more aware of the risks and hence more careful when using VIMs, especially on high-dimensional, small-sample and high complexity datasets

Concerted loop motion triggers induced fit of FepA to ferric enterobactin

Spectroscopic analyses of fluorophore-labeled Escherichia coli FepA described dynamic actions of its surface loops during binding and transport of ferric enterobactin (FeEnt). When FeEnt bound to fluoresceinated FepA, in living cells or outer membrane fragments, quenching of fluorophore emissions reflected conformational motion of the external vestibular loops. We reacted Cys sulfhydryls in seven surface loops (L2, L3, L4, L5, L7 L8, and L11) with fluorophore maleimides. The target residues had different accessibilities, and the labeled loops themselves showed variable extents of quenching and rates of motion during ligand binding. The vestibular loops closed around FeEnt in about a second, in the order L3 > L11 > L7 > L2 > L5 > L8 > L4. This sequence suggested that the loops bind the metal complex like the fingers of two hands closing on an object, by individually adsorbing to the iron chelate. Fluorescence from L3 followed a biphasic exponential decay as FeEnt bound, but fluorescence from all the other loops followed single exponential decay processes. After binding, the restoration of fluorescence intensity (from any of the labeled loops) mirrored cellular uptake that depleted FeEnt from solution. Fluorescence microscopic images also showed FeEnt transport, and demonstrated that ferric siderophore uptake uniformly occurs throughout outer membrane, including at the poles of the cells, despite the fact that TonB, its inner membrane transport partner, was not detectable at the poles

A Toolkit and Robust Pipeline for the Generation of Fosmid-Based Reporter Genes in C. elegans

Engineering fluorescent proteins into large genomic clones, contained within BACs or fosmid vectors, is a tool to visualize and study spatiotemporal gene expression patterns in transgenic animals. Because these reporters cover large genomic regions, they most likely capture all cis-regulatory information and can therefore be expected to recapitulate all aspects of endogenous gene expression. Inserting tags at the target gene locus contained within genomic clones by homologous recombination (“recombineering”) represents the most straightforward method to generate these reporters. In this methodology paper, we describe a simple and robust pipeline for recombineering of fosmids, which we apply to generate reporter constructs in the nematode C. elegans, whose genome is almost entirely covered in an available fosmid library. We have generated a toolkit that allows for insertion of fluorescent proteins (GFP, YFP, CFP, VENUS, mCherry) and affinity tags at specific target sites within fosmid clones in a virtually seamless manner. Our new pipeline is less complex and, in our hands, works more robustly than previously described recombineering strategies to generate reporter fusions for C. elegans expression studies. Furthermore, our toolkit provides a novel recombineering cassette which inserts a SL2-spliced intercistronic region between the gene of interest and the fluorescent protein, thus creating a reporter controlled by all 5′ and 3′ cis-acting regulatory elements of the examined gene without the direct translational fusion between the two. With this configuration, the onset of expression and tissue specificity of secreted, sub-cellular compartmentalized or short-lived gene products can be easily detected. We describe other applications of fosmid recombineering as well. The simplicity, speed and robustness of the recombineering pipeline described here should prompt the routine use of this strategy for expression studies in C. elegans

The Role of Growth Retardation in Lasting Effects of Neonatal Dexamethasone Treatment on Hippocampal Synaptic Function

BACKGROUND: Dexamethasone (DEX), a synthetic glucocorticoid, is commonly used to prevent or lessen the morbidity of chronic lung disease in preterm infants. However, evidence is now increasing that this clinical practice negatively affects somatic growth and may result in long-lasting neurodevelopmental deficits. We therefore hypothesized that supporting normal somatic growth may overcome the lasting adverse effects of neonatal DEX treatment on hippocampal function. METHODOLOGY/PRINCIPAL FINDINGS: To test this hypothesis, we developed a rat model using a schedule of tapering doses of DEX similar to that used in premature infants and examined whether the lasting influence of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance are correlated with the deficits in somatic growth. We confirmed that neonatal DEX treatment switched the direction of synaptic plasticity in hippocampal CA1 region, favoring low-frequency stimulation- and group I metabotropic glutamate receptor agonist (S)-3,5,-dihydroxyphenylglycine-induced long-term depression (LTD), and opposing the induction of long-term potentiation (LTP) by high-frequency stimulation in the adolescent period. The effects of DEX on LTP and LTD were correlated with an increase in the autophosphorylation of Ca(2+)/calmodulin-dependent protein kinase II at threonine-286 and a decrease in the protein phosphatase 1 expression. Neonatal DEX treatment resulted in a disruption of memory retention subjected to object recognition task and passive avoidance learning. The adverse effects of neonatal DEX treatment on hippocampal synaptic plasticity and memory performance of the animals from litters culled to 4 pups were significantly less than those for the 8-pup litters. However, there was no significant difference in maternal care between groups. CONCLUSION/SIGNIFICANCE: Our results demonstrate that growth retardation plays a crucial role in DEX-induced long-lasting influence of hippocampal function. Our findings suggest that therapeutic strategies designed to support normal development and somatic growth may exert beneficial effects to reduce lasting adverse effects following neonatal DEX treatment