Squaraine dyes are a class of organic dyes with strong and narrow absorption bands in the near-infrared. Despite high molar absorptivities and fluorescence quantum yields, these dyes have been less ...explored than other dye scaffolds due to their susceptibility to nucleophilic attack. Recent strategies in probe design including encapsulation, conjugation to biomolecules, and new synthetic modifications have seen squaraine dyes emerging into the forefront of biomedical imaging and other applications. Herein, we provide a concise overview of (1) the synthesis of symmetrical and unsymmetrical squaraine dyes, (2) the relationship between structure and photophysical properties of squaraine dyes, and (3) current applications of squaraine dyes in the literature. Given the recent successes at overcoming the limitations of squaraine dyes, they show high potential in biological imaging, in photodynamic and photothermal therapies, and as molecular sensors.
Carcinogenesis is a multistep process by which normal cells acquire genetic and epigenetic changes that result in cancer. In combination with host genetic susceptibility and environmental exposures, ...a prominent procarcinogenic role for the microbiota has recently emerged. In colorectal cancer (CRC), three nefarious microbes have been consistently linked to cancer development: (
a
) Colibactin-producing
Escherichia coli
initiates carcinogenic DNA damage, (
b
) enterotoxigenic
Bacteroides fragilis
promotes tumorigenesis via toxin-induced cell proliferation and tumor-promoting inflammation, and (
c
)
Fusobacterium nucleatum
enhances CRC progression through two adhesins, Fap2 and FadA, that promote proliferation and antitumor immune evasion and may contribute to metastases. Herein, we use these three prominent microbes to discuss the experimental evidence linking microbial activities to carcinogenesis and the specific mechanisms driving this stepwise process. Precisely defining mechanisms by which the microbiota impacts carcinogenesis at each stage is essential for developing microbiota-targeted strategies for the diagnosis, prognosis, and treatment of cancer.
There is much to learn about improving baffle designs to increase successful fish passage through culverts. A fish’s motivation to attempt entry into the culvert is essential. Upon entry, successful ...passage will largely depend on the physiological ability of the fish to navigate the entire culvert length. In this study, the motivation of brook trout (Salvelinus fontinalis (Mitchill, 1814)) and brown trout (Salmo trutta Linnaeus, 1758) to attempt ascent of an experimental flume, which mimics a roadway culvert left bare (smooth) or fitted with either spoiler or weir baffles, is assessed. Performance, measured as maximum distance of ascent within the flume, is also quantified. The bare flume was the most motivating for brook trout, and the weirs were most motivating for brown trout. As a rule, brown trout showed less motivation to stage attempts than brook trout, except within the weir baffle treatments. Performance was greatest in the weirs for smaller trout and in the spoiler baffles for larger trout. Our findings suggest that baffle form influences passage rates at road crossings in ways previously unknown and further stresses the importance of considering fish motivation and performance together when assessing the efficacy of baffle forms.
Small differences in the densities of a river confluence's tributaries (i.e. 0.5 kg m$^{-3}$) have been proposed to cause coherent streamwise-oriented vortices (SOVs) in its mixing interface. These ...secondary flow structures are thought to result from density-driven gravity currents being laterally confined between the converging flows. However, empirical evidence for density SOVs and the confined gravity current mechanism is lacking. To this end, experiments are carried out in a laboratory confluence permitting a spectrum of thermal density differences between its tributaries. Particle image velocimetry and laser-induced fluorescence are used simultaneously to study the mixing interface's dynamics. The sensitivity of the mixing interface's secondary flow structure to the confluence's momentum ratio and the magnitude of the density difference is evaluated. Density SOVs are confirmed in the mixing interface and are caused by the gravity currents being confined laterally as the opposing flows merge and accelerate downstream. The SOVs are largest and most coherent when the momentum of the dense channel is greater than that of the light channel. The dynamics of these secondary flow structures is strongly coupled to periodic vertically orientated Kelvin–Helmholtz instabilities. The striking similarities between the empirically reproduced SOVs herein and those recently observed at the Coaticook-Massawippi confluence (Quebec, Canada), despite a two-order magnitude difference in physical scale, suggest density SOVs are a scale-independent flow structure at confluences when specific, yet relatively common, hydraulic and density conditions align.
High-throughput RNA sequencing (RNA-seq) has become an instrumental assay for the analysis of multiple aspects of an organism's transcriptome. Further, the analysis of a biological specimen's ...associated microbiome can also be performed using RNA-seq data and this application is gaining interest in the scientific community. There are many existing bioinformatics tools designed for analysis and visualization of transcriptome data. Despite the availability of an array of next generation sequencing (NGS) analysis tools, the analysis of RNA-seq data sets poses a challenge for many biomedical researchers who are not familiar with command-line tools. Here we present RNA CoMPASS, a comprehensive RNA-seq analysis pipeline for the simultaneous analysis of transcriptomes and metatranscriptomes from diverse biological specimens. RNA CoMPASS leverages existing tools and parallel computing technology to facilitate the analysis of even very large datasets. RNA CoMPASS has a web-based graphical user interface with intrinsic queuing to control a distributed computational pipeline. RNA CoMPASS was evaluated by analyzing RNA-seq data sets from 45 B-cell samples. Twenty-two of these samples were derived from lymphoblastoid cell lines (LCLs) generated by the infection of naïve B-cells with the Epstein Barr virus (EBV), while another 23 samples were derived from Burkitt's lymphomas (BL), some of which arose in part through infection with EBV. Appropriately, RNA CoMPASS identified EBV in all LCLs and in a fraction of the BLs. Cluster analysis of the human transcriptome component of the RNA CoMPASS output clearly separated the BLs (which have a germinal center-like phenotype) from the LCLs (which have a blast-like phenotype) with evidence of activated MYC signaling and lower interferon and NF-kB signaling in the BLs. Together, this analysis illustrates the utility of RNA CoMPASS in the simultaneous analysis of transcriptome and metatranscriptome data. RNA CoMPASS is freely available at http://rnacompass.sourceforge.net/.
Despite significant efforts to translate nanotechnology for cancer application, lack of identification of biodistribution/accumulation of these nanovehicles in vivo remains a substantial barrier for ...successful implementation of theranostic nanoparticles in the clinic. The purpose of the study was to develop a tumor-targeted theranostic nanovehicle for pancreatic cancer detectable by multispectral optoacoustic tomography (MSOT). To improve the tumor specificity of our mesoporous silica nanoparticle (MSN), we utilized a dual targeting strategy: 1) an elevated tumor receptor, urokinase plasminogen activator receptor (UPAR), and 2) the acidic tumor microenvironment. The tumor specificity of the MSN particle was improved with the addition of both chitosan, targeting acidic pH, and urokinase plasminogen activator (UPA), targeting UPAR. Drug release assays confirmed pH responsive release of gemcitabine in vitro. The UPAR specific binding of MSN-UPA nanoparticles was confirmed by reduction in fluorescence signal following MSN-UPA nanoparticle treatment in UPAR positive cells blocked with a UPAR-blocking antibody. Based upon Indocyanine Green encapsulation within the nanoparticles, UPA ligand targeted MSNs demonstrated increased intensity compared to untargeted MSNs at both pH7.4 (7×) and 6.5 (20×); however the signal was much more pronounced at a pH of 6.5 using tissue phantoms (p<0.05). In vivo, MSN-UPA particles demonstrated orthotopic pancreatic tumor specific accumulation compared to liver or kidney as identified using multispectral optoacoustic tomography (p<0.05) and confirmed by ex vivo analysis. By tracking in vivo nanoparticle biodistribution with MSOT, it was shown that pH responsive, ligand targeted MSNs preferentially bind to pancreatic tumors for payload delivery.
Urokinase plasminogen activator (UPA) targeted mesoporous silica nanoparticles that selectively target UPA receptor (UPAR) positive pancreatic cancer cells facilitate tumor detection using multispectral optoacoustic tomography. Display omitted
This study characterizes the shear layer and associated vortex shedding around an isolated submerged pebble cluster in a gravel-bed river. The approach combines flow visualization and high frequency ...three-dimensional velocity (acoustic Doppler velocimeter) measurements. Two vortex shedding modes in the wake of the cluster were identified: A small scale high frequency initial instability mode and a lower frequency mode that scales with cluster height. The lower frequency mode arose from the intermittent interaction and amalgamation of the small-scale instability vortices. Reynolds shear stresses, velocity spectra, and coherence functions indicated a dominance of longitudinal-vertical shedding vortices in the wake of the cluster. Simultaneous flow visualization was required to determine the nature and behavior of the shedding modes. Quadrant analysis revealed that Q2 and Q4 events contributed 80% of the local longitudinal-vertical component Reynolds shear stress, and demonstrated a dominance of ejection events in the wake of the cluster. Through flow visualization, the behavior of the shear layer was seen to vertically expand and contract with the passage of Q2 and Q4 events, respectively.
Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these ...studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV.
In regenerative medicine, bone marrow is a promising source of mesenchymal stem cells (MSCs) for a broad range of cellular therapies. This research addresses a basic prerequisite to realize the ...therapeutic potential of MSCs by developing a novel high-capacity assay to quantify the clonal heterogeneity in potency that is inherent to MSC preparations. The assay utilizes a 96-well format to (1) classify MSCs according to colony-forming efficiency as a measure of proliferation capacity and trilineage potential to exhibit adipo-, chondro-, and osteogenesis as a measure of multipotency and (2) preserve a frozen template of MSC clones of known potency for future use. The heterogeneity in trilineage potential of normal bone marrow MSCs is more complex than previously reported: all eight possible categories of trilineage potential were detected. In this study, the average colony-forming efficiency of MSC preparations was 55-62%, and tripotent MSCs accounted for nearly 50% of the colony-forming cells. The multiple phenotypes detected in this study infer a more convoluted hierarchy of lineage commitment than described in the literature. Greater cell amplification, colony-forming efficiency, and colony diameter for tri- versus unipotent clones suggest that MSC proliferation may be a function of potency. CD146 may be a marker of multipotency, with approximately 2-fold difference in mean fluorescence intensity between tri- and unipotent clones. The significance of these findings is discussed in the context of the efficacy of MSC therapies. The in vitro assay described herein will likely have numerous applications given the importance of heterogeneity to the therapeutic potential of MSCs.
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