Abstract
Emission rates and properties of ice nucleating particles (INPs) are required for proper representation of aerosol–cloud interactions in atmospheric models. Few investigations have ...quantified marine INP emissions, a potentially important INP source for remote oceanic regions. Previous studies have suggested INPs in sea spray aerosol (SSA) are linked to oceanic biological activity. This proposed link was explored in this study by measuring INP emissions from nascent SSA during phytoplankton blooms during two mesocosm experiments. In a Marine Aerosol Reference Tank (MART) experiment, a phytoplankton bloom was produced with chlorophyll-a (Chl a) concentrations reaching 39 μg L−1, while Chl a concentrations more representative of natural ocean conditions were obtained during the Investigation into Marine Particle Chemistry and Transfer Science (IMPACTS; peak Chl a of 5 μg L−1) campaign, conducted in the University of California, San Diego, wave flume. Dynamic trends in INP emissions occurred for INPs active at temperatures > −30°C. Increases in INPs active between −25° and −15°C lagged the peak in Chl a in both studies, suggesting a consistent population of INPs associated with the collapse of phytoplankton blooms. Trends in INP emissions were also compared to aerosol composition, abundances of microbes, and enzyme activity. In general, increases in INP concentrations corresponded to increases in organic species in SSA and the emissions of heterotrophic bacteria, suggesting that both microbes and biomolecules contribute to marine INP populations. INP trends were not directly correlated with a single biological marker in either study. Direct measurements of INP chemistry are needed to accurately identify particles types contributing to marine INP populations.
Ice nucleating particles (INPs) are vital for ice initiation in, and precipitation from, mixed-phase clouds. A source of INPs from oceans within sea spray aerosol (SSA) emissions has been suggested ...in previous studies but remained unconfirmed. Here, we show that INPs are emitted using real wave breaking in a laboratory flume to produce SSA. The number concentrations of INPs from laboratory-generated SSA, when normalized to typical total aerosol number concentrations in the marine boundary layer, agree well with measurements from diverse regions over the oceans. Data in the present study are also in accord with previously published INP measurements made over remote ocean regions. INP number concentrations active within liquid water droplets increase exponentially in number with a decrease in temperature below 0 °C, averaging an order of magnitude increase per 5 °C interval. The plausibility of a strong increase in SSA INP emissions in association with phytoplankton blooms is also shown in laboratory simulations. Nevertheless, INP number concentrations, or active site densities approximated using “dry” geometric SSA surface areas, are a few orders of magnitude lower than corresponding concentrations or site densities in the surface boundary layer over continental regions. These findings have important implications for cloud radiative forcing and precipitation within low-level and midlevel marine clouds unaffected by continental INP sources, such as may occur over the Southern Ocean.
After conception and implementation of any new medical image processing algorithm, validation is an important step to ensure that the procedure fulfils all requirements set forth at the initial ...design stage. Although the algorithm must be evaluated on real data, a comprehensive validation requires the additional use of simulated data since it is impossible to establish ground truth with in vivo data. Experiments with simulated data permit controlled evaluation over a wide range of conditions (e.g., different levels of noise, contrast, intensity artefacts, or geometric distortion). Such considerations have become increasingly important with the rapid growth of neuroimaging, i.e., computational analysis of brain structure and function using brain scanning methods such as positron emission tomography and magnetic resonance imaging. Since simple objects such as ellipsoids or parallelepipedes do not reflect the complexity of natural brain anatomy, the authors present the design and creation of a realistic, high-resolution, digital, volumetric phantom of the human brain. This three-dimensional digital brain phantom is made up of ten volumetric data sets that define the spatial distribution for different tissues (e.g., grey matter, white matter, muscle, skin, etc.), where voxel intensity is proportional to the fraction of tissue within the voxel. The digital brain phantom can be used to simulate tomographic images of the head. Since the contribution of each tissue type to each voxel in the brain phantom is known, it can be used as the gold standard to test analysis algorithms such as classification procedures which seek to identify the tissue "type" of each image voxel. Furthermore, since the same anatomical phantom may be used to drive simulators for different modalities, it is the ideal tool to test intermodality registration algorithms. The brain phantom and simulated MR images have been made publicly available on the Internet (http://www.bic.mni.mcgill.ca/brainweb).
RNA interference (RNAi) mediated by short interfering RNAs (siRNAs) is a widely used method to analyze gene function. To use RNAi knockdown accurately to infer gene function, it is essential to ...determine the specificity of siRNA-mediated RNAi. We have assessed the specificity of 10 different siRNAs corresponding to the MEN1 gene by examining the expression of two additional genes, TP53 (p53) and CDKN1A (p21), which are considered functionally unrelated to menin but are sensitive markers of cell state. MEN1 RNA and corresponding protein levels were all reduced after siRNA transfection of HeLa cells, although the degree of inhibition mediated by individual siRNAs varied. Unexpectedly, we observed dramatic and significant changes in protein levels of p53 and p21 that were unrelated to silencing of the target gene. The modulations in p53 and p21 levels were not abolished on titration of the siRNAs, and similar results were obtained in three other cell lines; in none of the cell lines tested did we see an effect on the protein levels of actin. These data suggest that siRNAs can induce nonspecific effects on protein levels that are siRNA sequence dependent but that these effects may be difficult to detect until genes central to a pivotal cellular response, such as p53 and p21, are studied. We find no evidence that activation of the double-stranded RNA-triggered IFN-associated antiviral pathways accounts for these effects, but we speculate that partial complementary sequence matches to off-target genes may result in a micro-RNA-like inhibition of translation.
Proteasome inhibitors (PIs), namely bortezomib, have become a cornerstone therapy for multiple myeloma (MM), potently reducing tumor burden and inhibiting pathologic bone destruction. In clinical ...trials, carfilzomib, a next generation epoxyketone-based irreversible PI, has exhibited potent anti-myeloma efficacy and decreased side effects compared with bortezomib. Carfilzomib and its orally bioavailable analog oprozomib, effectively decreased MM cell viability following continual or transient treatment mimicking in vivo pharmacokinetics. Interactions between myeloma cells and the bone marrow (BM) microenvironment augment the number and activity of bone-resorbing osteoclasts (OCs) while inhibiting bone-forming osteoblasts (OBs), resulting in increased tumor growth and osteolytic lesions. At clinically relevant concentrations, carfilzomib and oprozomib directly inhibited OC formation and bone resorption in vitro, while enhancing osteogenic differentiation and matrix mineralization. Accordingly, carfilzomib and oprozomib increased trabecular bone volume, decreased bone resorption and enhanced bone formation in non-tumor bearing mice. Finally, in mouse models of disseminated MM, the epoxyketone-based PIs decreased murine 5TGM1 and human RPMI-8226 tumor burden and prevented bone loss. These data demonstrate that, in addition to anti-myeloma properties, carfilzomib and oprozomib effectively shift the bone microenvironment from a catabolic to an anabolic state and, similar to bortezomib, may decrease skeletal complications of MM.
ABSTRACT
In this paper, we present the X-ray analysis of Sloan Digital Sky Survey DR8 redMaPPer (SDSSRM) clusters using data products from the XMM Cluster Survey (XCS). In total, 1189 SDSSRM clusters ...fall within the XMM–Newton footprint. This has yielded 456 confirmed detections accompanied by X-ray luminosity (LX) measurements. Of these clusters, 381 have an associated X-ray temperature measurement (TX). This represents one of the largest samples of coherently derived cluster TX values to date. Our analysis of the X-ray observable to richness scaling relations has demonstrated that scatter in the TX–λ relation is roughly a third of that in the LX–λ relation, and that the LX–λ scatter is intrinsic, i.e. will not be significantly reduced with larger sample sizes. Analysis of the scaling relation between LX and TX has shown that the fits are sensitive to the selection method of the sample, i.e. whether the sample is made up of clusters detected ‘serendipitously’ compared to those deliberately targeted by XMM. These differences are also seen in the LX–λ relation and, to a lesser extent, in the TX–λ relation. Exclusion of the emission from the cluster core does not make a significant impact on the findings. A combination of selection biases is a likely, but yet unproven, reason for these differences. Finally, we have also used our data to probe recent claims of anisotropy in the LX–TX relation across the sky. We find no evidence of anistropy, but stress this may be masked in our analysis by the incomplete declination coverage of the SDSS.
Human epidermal growth factor 2 (HER2/ERBB2) is frequently amplified/mutated in cancer. The tyrosine kinase inhibitors (TKIs) lapatinib, neratinib, and tucatinib are FDA-approved for the treatment of ...HER2-positive breast cancer. Direct comparisons of the preclinical efficacy of the TKIs have been limited to small-scale studies. Novel biomarkers are required to define beneficial patient populations.
In this study, the anti-proliferative effects of the three TKIs were directly compared using a 115 cancer cell line panel. Novel TKI response/resistance markers were identified through cross-analysis of drug response profiles with mutation, gene copy number and expression data.
All three TKIs were effective against HER2-amplified breast cancer models; neratinib showing the most potent activity, followed by tucatinib then lapatinib. Neratinib displayed the greatest activity in HER2-mutant and EGFR-mutant cells. High expression of HER2, VTCN1, CDK12, and RAC1 correlated with response to all three TKIs. DNA damage repair genes were associated with TKI resistance. BRCA2 mutations were correlated with neratinib and tucatinib response, and high expression of ATM, BRCA2, and BRCA1 were associated with neratinib resistance.
Neratinib was the most effective HER2-targeted TKI against HER2-amplified, -mutant, and EGFR-mutant cell lines. This analysis revealed novel resistance mechanisms that may be exploited using combinatorial strategies.
Compared with systemic antibiotic therapy, the topical or local delivery of an antibiotic has many potential advantages. However, local antibiotics at the surgical site have received very limited ...approval in any of the surgical prophylaxis consensus guidelines that we are aware of. A review of the literature was carried out through searches of peer-reviewed publications in PubMed in the English language over a 30 year period between January 1980 and May 2010. Both retrospective and prospective studies were included, as well as meta-analyses. With regard to defining 'topical' or 'local' antibiotic application, the application of an antibiotic solution to the surgical site intraoperatively or immediately post-operatively was included. A number of surgical procedures have been shown to significantly benefit from perioperative topical prophylaxis, e.g. joint arthroplasty, cataract surgery and, possibly, breast augmentation. In obese patients undergoing abdominal surgery, topical surgical prophylaxis is also proven to be beneficial. The selective use of topical antibiotics as surgical prophylaxis is justified for specific procedures, such as joint arthroplasty, cataract surgery and, possibly, breast augmentation. In selective cases, such as obese patients undergoing abdominal surgery, topical surgical prophylaxis is also proven to be beneficial. Apart from these specific indications, the evidence for use of topical antibiotics in surgery is lacking in conclusive randomized controlled trials.
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