These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.
In a series of p H 7 continuous-flow column experiments, removal of the bacteriophage MS-2 by attachment to silica beads had a strong, systematic dependence on the amount of hydrophobic surface present on the beads. With no hydrophobic surface, removal of phage at p H 5 was much greater than at pH 7. Release of attached phage at both pH values did occur, but was slow; breakthrough curves exhibited tailing. Poliovirus attached to silica beads at pH 5.5 much more than at pH 7.0, and attachment was also slowly reversible. Time scales for phage and poliovirus attachment were of the order of hours. The sticking efficiency factor (a), reflecting microscale physicochemical influences on virus attachment, was in the range of 0.0007-0.02. Phage release was small but measurable under steady state conditions. Release was enhanced by lowering ionic strength and by introducing beef extract, a high-ionic-strength protein solution. Results show that viruses experience reversible attachment/detachment (sometimes termed sorption), that large chemical perturbations are needed to induce rapid virus detachment, and that viruses should be quite mobile in sandy porous media. Even small amounts of hydrophobic organic material in the porous media (>0.001%) can retard virus transport.
SLC4A11 is a NH
3
sensitive membrane transporter with H
+
channel-like properties that facilitates Glutamine catabolism in Human and Mouse corneal endothelium (CE). Loss of SLC4A11 activity induces oxidative stress and cell death, resulting in Congenital Hereditary Endothelial Dystrophy (CHED) with corneal edema and vision loss. However, the mechanism by which SLC4A11 prevents ROS production and protects CE is unknown. Here we demonstrate that SLC4A11 is localized to the inner mitochondrial membrane of CE and SLC4A11 transfected PS120 fibroblasts, where it acts as an NH
3
-sensitive mitochondrial uncoupler that enhances glutamine-dependent oxygen consumption, electron transport chain activity, and ATP levels by suppressing damaging Reactive Oxygen Species (ROS) production. In the presence of glutamine,
Slc4a11
−/−
(KO) mouse CE generate significantly greater mitochondrial superoxide, a greater proportion of damaged depolarized mitochondria, and more apoptotic cells than WT. KO CE can be rescued by MitoQ, reducing NH
3
production by GLS1 inhibition or dimethyl αKetoglutarate supplementation, or by BAM15 mitochondrial uncoupling.
Slc4a11
KO mouse corneal edema can be partially reversed by αKetoglutarate eye drops. Moreover, we demonstrate that this role for SLC4A11 is not specific to CE cells, as SLC4A11 knockdown in glutamine-addicted colon carcinoma cells reduced glutamine catabolism, increased ROS production, and inhibited cell proliferation. Overall, our studies reveal a unique metabolic mechanism that reduces mitochondrial oxidative stress while promoting glutamine catabolism.
Abstract. A two-well forced-gradient experiment involving virus and microsphere transport was carried out in a sandy aquifer in Borden, Ontario, Canada. Virus traveled at least a few meters in the experiment, but virus concentrations at observation points 1 and 2.54 rn away from the injection well were a small fraction of those injected. A simplified planar radial advection-dispersion equation with constant dispersivity, coupled with equilibrium and reversible first-order mass transfer, was found to be adequate to simulate the attachment and transport process. During the experiment a short-duration injection of high-pH water was also made, which caused detachment of previously attached viruses. For simulating this detachment and associated transport, the same transport and masstransfer equations were used; but all rate parameters were varied as groundwater p H changed from 7.4 to 8.4 and then back to 7.4. The physicochemical parameters obtained from fitting breakthrough curves at one sampling well were used to predict those at another well downstream. However, laboratory-determined parameters overpredicted colloid removal. The predicted pattern and timing of biocolloid breakthrough was in agreement with observations, though the data showed a more-disperse breakthrough than expected from modeling. Though clearly not an equilibrium process, retardation involving a dynamic steady state between attachment and detachment was nevertheless a major determinant of transport versus retention of virus in this field experiment.
Transport of the bacteriophage PRD‐1, bacteria, and latex microspheres was studied in a sandy aquifer under natural‐gradient conditions. The field injection was carried out at the U.S. Geological Survey's Toxic Substances Hydrology research site on Cape Cod. The three colloids and a salt tracer (Br−) moved along the same path. There was significant attenuation of the phage, with PRD‐1 peak concentrations less than 0.001 percent of Br− peaks 6 m from the source; but the low detection limit (one per ml) enabled tracking movement of the PRD‐1 plume for 12 m downgradient over the 25‐day experiment. Attenuation of phage was apparently due to retention on soil particles (adsorption). Attenuation of bacteria and microspheres was less, with peak concentrations 6 m from the source on the order of 10 and 0.4 percent of Br−, respectively. Injection of a high‐pH pulse of water 20 days into the experiment resulted in significant remobilization of retained phage, demonstrating that attached phage remained viable, and that PRD‐1 attachment to and detachment from the sandy soil particles was highly pH dependent. Phage behavior in this experiment, i.e. attenuation at pH 5.7 and rapid resuspension at pH 6–8, was consistent with that observed previously in laboratory column studies. Results illustrate that biocolloids travel in a fairly narrow plume in sandy (relatively homogeneous) media, with virus concentrations dropping below detection limit several meters away from the source; bacteria concentrations above detection limits can persist over longer distances.
Human corneal endothelial cells (HCEnCs) form a monolayer of hexagonal cells whose main function is to maintain corneal clarity by regulating corneal hydration. HCEnCs are derived from neural crest and are arrested in the post-mitotic state. Thus cell loss due to aging or corneal endothelial disorders leads to corneal edema and blindness–the leading indication for corneal transplantation. Here we show the existence of morphologically distinct subpopulations of HCEnCs that are interspersed among primary cells and exhibit enhanced self-renewal competence and lack of phenotypic signs of cellular senescence. Colonies of these uniform and hexagonal HCEnCs (HCEnC-21) were selectively isolated and demonstrated high proliferative potential that was dependent on endogenous upregulation of telomerase and cyclin D/CDK4. Further transduction of HCEnC-21 with telomerase yielded a highly proliferative corneal endothelial cell line (HCEnT-21T) that was devoid of oncogenic transformation and retained critical corneal endothelial cell characteristics and functionality. This study will significantly impact the fields of corneal cell biology and regenerative medicine.
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