Time‐dependent viscosity of structured clay suspensions under a fixed shear was revealed in the prepared slurry samples of clay lenses from the Athabasca oil sands deposit, differing from thixotropic ...or rheopectic suspensions. At a lower salt (Na or Ca) concentration, the viscosity oscillated with time, which was slowly damped with increasing salt concentrations. The viscosity increased without reaching a maximum plateau, even after a run of a few hours. At 1000 ppm Na concentration, a maximum viscosity was reached, followed by viscosity fluctuation within a narrow range to approach an equilibrium value with time. Both sample ageing and shear history affected the slurry viscosity. It was speculated that the Brownian motion of colloidal clay particles and the applied shear induced rearrangement and continued formation of clay microstructures with time, due to the rotation of anisotropic colloidal clay particles under simple shear flow. Its implications to oil sands research and operation were briefly discussed.
Effect of water flow velocity (≤3 m/s) on bubbles detaching from bitumen was examined in a water channel at room temperature. The results showed different behaviours of bubble–bitumen detachment for ...different sizes of bubbles. With increasing water flow speed, a larger bubble (>0.15–0.2 cm) underwent the following steps before detaching from the bitumen layer: deformation; neck formation; the bubble broke up from the neck, with the top portion sheared away, leaving the bottom portion as a small bubble stuck to bitumen; and then, the small bubble detached from the bitumen and was carried away by further increasing water flow. Smaller bubbles (<0.1–0.15 cm) detached from bitumen after deformation without breaking up, with increasing water flow. An empirical correlation between the size of bubbles detaching from bitumen with water flow velocity/shear rate was established. At a flow velocity of 3 m/s, only bubbles smaller than 250–300 μm might be able to stay attached to bitumen, or a shear rate higher than 2500 s−1 is needed to detach a 250–300 μm bubble from bitumen.
For mAbs to be viable therapeutics, they must be formulated to have low viscosity, be chemically stable, and have normal in vivo clearance rates. We explored these properties by observing ...correlations of up to 60 different antibodies of the IgG1 isotype. Unexpectedly, we observe significant correlations with simple physical properties obtainable from antibody sequences and by molecular dynamics simulations of individual antibody molecules. mAbs viscosities increase strongly with hydrophobicity and charge dipole distribution and decrease with net charge. Fast clearance correlates with high hydrophobicities of certain complementarity determining regions and with high positive or high negative net charge. Chemical degradation from tryptophan oxidation correlates with the average solvent exposure time of tryptophan residues. Aspartic acid isomerization rates can be predicted from solvent exposure and flexibility as determined by molecular dynamics simulations. These studies should aid in more rapid screening and selection of mAb candidates during early discovery.
Significance mAbs are increasingly being used for treatment of chronic diseases wherein the subcutaneous delivery route is preferred to enable self-administration and at-home use. To deliver high doses (several hundred milligrams) through a small volume (∼1 mL) into the subcutaneous space, mAb solutions need to have low viscosity. Concomitantly, acceptable chemical stability is required for adequate shelf life, and normal in vivo clearance is needed for less frequent dosing. We propose in silico tools that provide rapid assessment of atypical behavior of mAbs (high viscosity, chemical degradation, and fast plasma clearance), which are simply predicted from sequence and/or structure-derived parameters. Such analysis will greatly improve the probability of success to move mAb-based therapeutics efficiently into clinical development and ultimately benefit patients.
Effect of salts (NaCl and CaCl2) on dynamic bubble nucleation on hydrophobic bitumen and silanated glass in air‐supersaturated water was examined using an autoclave at air saturation pressure of ...700 kPa and temperature of 80°C. The results showed that at a low salt concentration, there was virtually no difference in the sizes of bubbles nucleated on the surface (0.06‐0.2 cm in diameter), as compared to the cases without salt addition. At a higher salt concentration (0.2 M CaCl2, or 0.3 M NaCl), the size of bubbles nucleated on the surfaces reduced drastically (more than 10‐fold smaller), with the surface being entirely frosted with small bubbles lined up neatly. The observed sizes of surface bubbles were up to more than 3600 times larger for the cases without salts, and 600 times larger at the high salt concentrations, than the critical equilibrium bubble diameter under given test conditions (~328 nm). Possible reasons for the observed phenomena were briefly discussed.
Current water‐based oil sands extraction operations are unsustainable, due to their consumption of large quantities of water and energy, generation of large volumes of fluid fine tailings, and rapid ...expansion of tailing ponds. From a brief analysis of the historical evolution of water‐based oil sands extraction, it has been identified that the use of conventional dispersed air flotation to recover liberated bitumen from oil sand slurries is mainly responsible for the high consumption of water required and the fluid fine tailings generated. Based on mineral flotation principles, a new concept is proposed, whereby water‐based oil sands extraction is simplified as a process of transferring hydrophobic bitumen from hydrophilic surfaces (sands) to hydrophobic surfaces (bitumen carriers). Compared to existing bitumen extraction technologies, bitumen liberation from sands is accelerated by attrition/scrubbing, and the liberated bitumen is recovered from the oil sand slurry by hydrophobic coagulation and heavy media separation. This concept is verified from preliminary laboratory tests for processing (above) average grade oil sands. The water required is significantly reduced from 100 to 150 wt% of the ores processed (as seen in current commercial operations) to 30‐40 wt% of the ores. Virtually no fluid fine tailings are generated, with the potential of eliminating tailing ponds. The tailings produced after bitumen extraction are paste‐like, containing >60 wt% solids, which can be directly disposed of in the mining pit, with little or no further treatment. Future research is needed to justify and refine the concept in large‐scale tests and engineer it into commercial operations.
Bitumen flotation hydrodynamics in water‐based oil sand extraction is critically reviewed by comparing aeration of oil sand slurries with mineral flotation. The role of the two‐stage particle‐bubble ...attachment model in flotation is emphasized as a means to accelerate bitumen flotation recovery. It involves the generation of micro/nanobubbles and their frosting on hydrophobic bitumen droplets, followed by their attachment to a flotation‐size bubble via its coalescence with the nanobubbles frosted on the bitumen. Nanobubble generation by hydrodynamic cavitation demonstrates that the size of nanobubbles can be reduced, and the number of nanobubbles increased by fast liquid flow, intensified agitation, high dissolved gas content and surfactant concentration. The mechanism of pre‐existing gas nuclei in enhancing nanobubble generation by cavitation is utilized to produce a large volume of stabilized nanobubbles for practical flotation, by continuously recirculating the stream through a gas saturation tank or a cavitation tube. The aeration of oil sand slurries in hydrotransport pipelines is analyzed based on its similarity to dissolved air flotation. Bitumen extraction recovery increased significantly with the presence of nanobubbles in the system. The role of improved flotation hydrodynamics in bitumen recovery is briefly discussed in terms of the Suncor operation using flotation columns to process oil sand middling streams. Future research should be directed at understanding bitumen flotation kinetics, optimizing size ranges of nanobubbles for maximized flotation recovery, minimizing wearing of cavitation tubes in industrial operations, and intensifying the role of in‐situ nanobubble nucleation on hydrophobic particles/bitumen droplets in flotation, especially for bitumen extraction from underperforming oil sands.
The morbidity and mortality rates of calcific aortic valve disease (CAVD) remain high while treatment options are limited. Here, we evaluated the role and therapeutic value of dual-specificity ...phosphatase 26 (DUSP26) in CAVD.
Microarray profiling of human calcific aortic valves and normal controls demonstrated that DUSP26 was significantly up-regulated in calcific aortic valves. ApoE-/- mice fed a normal diet or a high cholesterol diet (HCD) were infected with adeno-associated virus serotype 2 carrying DUSP26 short-hairpin RNA to examine the effects of DUSP26 silencing on aortic valve calcification. DUSP26 silencing ameliorated aortic valve calcification in HCD-treated ApoE-/- mice, as evidenced by reduced thickness and calcium deposition in the aortic valve leaflets, improved echocardiographic parameters (decreased peak transvalvular jet velocity and mean transvalvular pressure gradient, as well as increased aortic valve area), and decreased levels of osteogenic markers (Runx2, osterix, and osteocalcin) in the aortic valves. These results were confirmed in osteogenic medium-induced human valvular interstitial cells. Immunoprecipitation, liquid chromatography-tandem mass spectrometry, and functional assays revealed that dipeptidyl peptidase-4 (DPP4) interacted with DUSP26 to mediate the procalcific effects of DUSP26. High N6-methyladenosine levels up-regulated DUSP26 in CAVD; in turn, DUSP26 activated DPP4 by antagonizing mouse double minute 2-mediated ubiquitination and degradation of DPP4, thereby promoting CAVD progression.
DUSP26 promotes aortic valve calcification by inhibiting DPP4 degradation. Our findings identify a previously unrecognized mechanism of DPP4 up-regulation in CAVD, suggesting that DUSP26 silencing or inhibition is a viable therapeutic strategy to impede CAVD progression.
Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC) inhibitor sodium butyrate (NaB) has been demonstrated to improve memory performance and ...rescue the neurodegeneration of several Alzheimer's Disease (AD) mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO) mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice. We found that chronic NaB treatment significantly restored contextual memory but did not alter cued memory in cDKO mice while such an effect was not permanent after treatment withdrawal. We further revealed that NaB treatment did not rescue reduced synaptic numbers and cortical shrinkage in cDKO mice, but significantly increased the neurogenesis in subgranular zone of dentate gyrus (DG). We also observed that tau hyperphosphorylation and inflammation related protein glial fibrillary acidic protein (GFAP) level were decreased in cDKO mice by NaB. Furthermore, GO and pathway analysis for the RNA-Seq data demonstrated that NaB treatment induced enrichment of transcripts associated with inflammation/immune processes and cytokine-cytokine receptor interactions. RT-PCR confirmed that NaB treatment inhibited the expression of inflammation related genes such as S100a9 and Ccl4 found upregulated in the brain of cDKO mice. Surprisingly, the level of brain histone acetylation in cDKO mice was dramatically increased and was decreased by the administration of NaB, which may reflect dysregulation of histone acetylation underlying memory impairment in cDKO mice. These results shed some lights on the possible molecular mechanisms of HDAC inhibitor in alleviating the neurodegenerative phenotypes of cDKO mice and provide a promising target for treating AD.
pathogenic variants are implicated in multiple types of congenital heart defects including hypoplastic left heart syndrome, where the left ventricle is underdeveloped. It is unknown how
regulates ...human cardiac cell lineage determination and cardiomyocyte proliferation. In addition, mechanisms by which
pathogenic variants lead to ventricular hypoplasia in hypoplastic left heart syndrome remain elusive.
CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 genome editing was utilized to delete
in human induced pluripotent stem cells. Cardiac differentiation was carried out by sequential modulation of WNT signaling, and
knockout and wild-type differentiating cells were collected at day 0, 2, 5, 10, 14, and 30 for single-cell RNA-seq.
Human
knockout induced pluripotent stem cells are able to generate functional cardiomyocytes and endothelial cells, suggesting that NOTCH1 is not required for mesoderm differentiation and cardiovascular development in vitro. However, disruption of NOTCH1 blocks human ventricular-like cardiomyocyte differentiation but promotes atrial-like cardiomyocyte generation through shortening the action potential duration.
deficiency leads to defective proliferation of early human cardiomyocytes, and transcriptomic analysis indicates that pathways involved in cell cycle progression and mitosis are downregulated in
knockout cardiomyocytes. Single-cell transcriptomic analysis reveals abnormal cell lineage determination of cardiac mesoderm, which is manifested by the biased differentiation toward epicardial and second heart field progenitors at the expense of first heart field progenitors in
knockout cell populations.
is essential for human ventricular-like cardiomyocyte differentiation and proliferation through balancing cell fate determination of cardiac mesoderm and modulating cell cycle progression. Because first heart field progenitors primarily contribute to the left ventricle, we speculate that pathogenic
variants lead to biased differentiation of first heart field progenitors, blocked ventricular-like cardiomyocyte differentiation, and defective cardiomyocyte proliferation, which collaboratively contribute to left ventricular hypoplasia in hypoplastic left heart syndrome.
Abstract
Current water‐based oil sands extraction operations are unsustainable, due to their consumption of large quantities of water and energy, generation of large volumes of fluid fine tailings, ...and rapid expansion of tailing ponds. From a brief analysis of the historical evolution of water‐based oil sands extraction, it has been identified that the use of conventional dispersed air flotation to recover liberated bitumen from oil sand slurries is mainly responsible for the high consumption of water required and the fluid fine tailings generated. Based on mineral flotation principles, a new concept is proposed, whereby water‐based oil sands extraction is simplified as a process of transferring hydrophobic bitumen from hydrophilic surfaces (sands) to hydrophobic surfaces (bitumen carriers). Compared to existing bitumen extraction technologies, bitumen liberation from sands is accelerated by attrition/scrubbing, and the liberated bitumen is recovered from the oil sand slurry by hydrophobic coagulation and heavy media separation. This concept is verified from preliminary laboratory tests for processing (above) average grade oil sands. The water required is significantly reduced from 100 to 150 wt% of the ores processed (as seen in current commercial operations) to 30‐40 wt% of the ores. Virtually no fluid fine tailings are generated, with the potential of eliminating tailing ponds. The tailings produced after bitumen extraction are paste‐like, containing >60 wt% solids, which can be directly disposed of in the mining pit, with little or no further treatment. Future research is needed to justify and refine the concept in large‐scale tests and engineer it into commercial operations.
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