The interaction between galloping and Kármán-vortex resonance for long rectangular cylinders is a crucial issue in flow-induced vibration, since this type of instability can cause catastrophic ...oscillations of structures or structural elements exposed to wind. Nevertheless, the models for galloping and vortex-induced vibrations fail to predict the onset of the excitation and its evolution with the flow speed. The main goal of this work is to clarify the most relevant features of the VIV–galloping instability for structures with rectangular cross section and to outline the parameters that control the phenomenon. First, this is pursued through an extensive literature review concerning two- and three-dimensional rectangular prisms with a side ratio in the range 1–2, which shows the complexity of the issue and the need for further investigations. Then, the results of new wind tunnel tests in smooth flow on a two-dimensional rectangular 3:2 cylinder were provided. This cross section was found very prone to instability and large-amplitude vibrations were observed also for high values of the Scruton number (product of non-dimensional mass times damping) and relatively low wind speeds. Also, for low Scruton numbers, the paper underscores the possibility to observe non-negligible excitation at low wind speed due to secondary vortex-resonance. Finally, the non-conservativeness of the values provided by Eurocode 1 for the galloping stability parameter and the Strouhal number is discussed.
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•Extensive literature review on the VIV–galloping instability of rectangular cylinders.•Large database for the galloping stability parameter of rectangular sections.•Experiments show the proclivity to VIV–galloping interaction of a rectangular 3:2 cylinder.•This interaction may foster a galloping-type instability at low reduced wind speed.•Eurocode 1 provides non-conservative data about galloping of rectangular sections.
The gut microbiota affects the physiology and metabolism of animals and its alteration can lead to diseases such as gut dysplasia or metabolic disorders. Several reports have shown that the immune ...system plays an important role in shaping both bacterial community composition and abundance in
, and that immune deficit, especially during aging, negatively affects microbiota richness and diversity. However, there has been little study at the effector level to demonstrate how immune pathways regulate the microbiota. A key set of
immune effectors are the antimicrobial peptides (AMPs), which confer defense upon systemic infection. AMPs and lysozymes, a group of digestive enzymes with antimicrobial properties, are expressed in the gut and are good candidates for microbiota regulation. Here, we take advantage of the model organism Drosophila melanogaster to investigate the role of AMPs and lysozymes in regulation of gut microbiota structure and diversity. Using flies lacking AMPs and newly generated lysozyme mutants, we colonized gnotobiotic flies with a defined set of commensal bacteria and analyzed changes in microbiota composition and abundance in vertical transmission and aging contexts through 16S rRNA gene amplicon sequencing. Our study shows that AMPs and, to a lesser extent, lysozymes are necessary to regulate the total and relative abundance of bacteria in the gut microbiota. We also decouple the direct function of AMPs from the immune deficiency (IMD) signaling pathway that regulates AMPs but also many other processes, more narrowly defining the role of these effectors in the microbial dysbiosis observed in IMD-deficient flies upon aging.
This study advances current knowledge in the field of host-microbe interactions by demonstrating that the two families of immune effectors, antimicrobial peptides and lysozymes, actively regulate the gut microbiota composition and abundance. Consequences of the loss of these antimicrobial peptides and lysozymes are exacerbated during aging, and their loss contributes to increased microbiota abundance and shifted composition in old flies. This work shows that immune effectors, typically associated with resistance to pathogenic infections, also help shape the beneficial gut community, consistent with the idea that host-symbiont interactions use the same "language" typically associated with pathogenesis.
Networks are typically visualized with force-based or spectral layouts. These algorithms lack reproducibility and perceptual uniformity because they do not use a node coordinate system. The layouts ...can be difficult to interpret and are unsuitable for assessing differences in networks. To address these issues, we introduce hive plots (http://www.hiveplot.com) for generating informative, quantitative and comparable network layouts. Hive plots depict network structure transparently, are simple to understand and can be easily tuned to identify patterns of interest. The method is computationally straightforward, scales well and is amenable to a plugin for existing tools.
BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-κB signaling. RNA-seq data have recently shown that BCL2 is the ...most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.
Nearly half of the earth's photosynthetically fixed carbon derives from the oceans. To determine global and region specific rates, we rely on models that estimate marine net primary productivity ...(NPP) thus it is essential that these models are evaluated to determine their accuracy. Here we assessed the skill of 21 ocean color models by comparing their estimates of depth-integrated NPP to 1156 in situ 14C measurements encompassing ten marine regions including the Sargasso Sea, pelagic North Atlantic, coastal Northeast Atlantic, Black Sea, Mediterranean Sea, Arabian Sea, subtropical North Pacific, Ross Sea, West Antarctic Peninsula, and the Antarctic Polar Frontal Zone. Average model skill, as determined by root-mean square difference calculations, was lowest in the Black and Mediterranean Seas, highest in the pelagic North Atlantic and the Antarctic Polar Frontal Zone, and intermediate in the other six regions. The maximum fraction of model skill that may be attributable to uncertainties in both the input variables and in situ NPP measurements was nearly 72%. On average, the simplest depth/wavelength integrated models performed no worse than the more complex depth/wavelength resolved models. Ocean color models were not highly challenged in extreme conditions of surface chlorophyll-a and sea surface temperature, nor in high-nitrate low-chlorophyll waters. Water column depth was the primary influence on ocean color model performance such that average skill was significantly higher at depths greater than 250 m, suggesting that ocean color models are more challenged in Case-2 waters (coastal) than in Case-1 (pelagic) waters. Given that in situ chlorophyll-a data was used as input data, algorithm improvement is required to eliminate the poor performance of ocean color NPP models in Case-2 waters that are close to coastlines. Finally, ocean color chlorophyll-a algorithms are challenged by optically complex Case-2 waters, thus using satellite-derived chlorophyll-a to estimate NPP in coastal areas would likely further reduce the skill of ocean color models.
A new generation of sequencing technologies, from Illumina/Solexa, ABI/SOLiD, 454/Roche, and Helicos, has provided unprecedented opportunities for high-throughput functional genomic research. To ...date, these technologies have been applied in a variety of contexts, including whole-genome sequencing, targeted resequencing, discovery of transcription factor binding sites, and noncoding RNA expression profiling. This review discusses applications of next-generation sequencing technologies in functional genomics research and highlights the transforming potential these technologies offer.
Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data ...provided by whole genome and transcriptome sequencing and analysis (WGTA) presents an opportunity to align a much larger proportion of patients to therapies.
Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number, and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected.
Clinically actionable targets were identified for 83% of patients, 37% of whom received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, PARP inhibitors, and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%), and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies.
Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.
NCT02155621
•A prospective study of 570 patients used whole genome and transcriptome analysis (WGTA) for real-time treatment options•Of 248 WGTA-informed treatments, 46% resulted in clinical benefit to the patient•RNA expression information was as valuable as DNA-based information for selecting treatments with clinical benefit•Integrated data informs selection of standard-of-care therapies, clinical trial enrollment and off-label use•This study supports the use of whole genome and transcriptome analysis in clinical cancer care
Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized ...OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.
The hematopoietic system produces a large number of highly specialized cell types that are derived through a hierarchical differentiation process from a common stem cell population. miRNAs are ...critical players in orchestrating this differentiation. Here, we report the development and application of a high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles for 27 phenotypically distinct cell populations isolated from normal adult mouse hematopoietic tissues. A total of 80,000 RT-qPCR assays were used to map the landscape of miRNA expression across the hematopoietic hierarchy, including rare progenitor and stem cell populations. We show that miRNA profiles allow for the direct inference of cell lineage relations and functional similarity. Our analysis reveals a close relatedness of the miRNA expression patterns in multipotent progenitors and stem cells, followed by a major reprogramming upon restriction of differentiation potential to a single lineage. The analysis of miRNA expression in single hematopoietic cells further demonstrates that miRNA expression is very tightly regulated within highly purified populations, underscoring the potential of single-cell miRNA profiling for assessing compartment heterogeneity.
NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers ...beyond lung has been shown.
Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization.
Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4–NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1–NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib.
These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin.
Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).
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