Oklahoma Youth as Consumers

Housing, Design and Consumer Resource

CRISPR-Cas9 mediated cell line engineering of apoptosis pathways increases antibody expression with site-specific modifications for antibody drug conjugation

New generation of antibody drug conjugates (ADCs) have expanded the repertoire of antibody drugs in the clinic and the market for cancer and inflammation indications by using highly stable linkers to attach potent small-molecule drug to various targeting antibodies. The drug and site of drug linkage to the antibody can have profound impact on the physiochemical properties and pharmacological profile of the ADC. Ambrx has developed a technology, Eukaryotic Chemical Orthogonal Directed Engineering (EuCODE), which allows non-natural amino acids with diverse physicochemical and biological properties to be genetically encoded and site-specifically incorporated into proteins/antibodies in mammalian cells. The non-natural amino acid provides a handle for the attachment of a small-molecule drug to generate homogenous ADC with a defined Drug-to-Antibody Ratio (DAR). To establish a CHO expression system for high production of monoclonal antibodies (mAbs) containing non-natural amino acids, we successfully generated a EuCODE platform cell line stably expressing engineered amber suppressor tRNA and its cognate tRNA synthetase specific for non-natural amino acid para-acetyl phenylalanine (pAF). When transfected with antibody of interest engineered with amber nonsense codon (TAG) at selected sites suitable for drug conjugation, this EuCODE platform cell line generates stable cell lines producing pAF containing mAbs for site-specifically conjugated ADC. In order to improve production titers of pAF containing antibody and achieve a robust platform, the platform cell line and stable cell lines were further evolved using CRISPR/Cas9 genome editing technology to sequentially knock out selected genes in glutamine synthesis and apoptosis pathways to improve selection efficiency and prevent loss of viable cell mass in production cultures, respectively. Inhibition of apoptosis pathway leads to dramatic increase in viable cell mass and results in extended production time and increased productivity. Phenotypic and genetic properties of these CRISPR engineered cell lines and product quality of the antibody will be discussed in the context of using the platform to develop a commercial manufacturing cell line

Cognitive function and mood at high altitude following acclimatization and use of supplemental oxygen and adaptive servoventilation sleep treatments.

Impairments in cognitive function, mood, and sleep quality occur following ascent to high altitude. Low oxygen (hypoxia) and poor sleep quality are both linked to impaired cognitive performance, but their independent contributions at high altitude remain unknown. Adaptive servoventilation (ASV) improves sleep quality by stabilizing breathing and preventing central apneas without supplemental oxygen. We compared the efficacy of ASV and supplemental oxygen sleep treatments for improving daytime cognitive function and mood in high-altitude visitors (N = 18) during acclimatization to 3,800 m. Each night, subjects were randomly provided with ASV, supplemental oxygen (SpO2 > 95%), or no treatment. Each morning subjects completed a series of cognitive function tests and questionnaires to assess mood and multiple aspects of cognitive performance. We found that both ASV and supplemental oxygen (O2) improved daytime feelings of confusion (ASV: p < 0.01; O2: p < 0.05) and fatigue (ASV: p < 0.01; O2: p < 0.01) but did not improve other measures of cognitive performance at high altitude. However, performance improved on the trail making tests (TMT) A and B (p < 0.001), the balloon analog risk test (p < 0.0001), and the psychomotor vigilance test (p < 0.01) over the course of three days at altitude after controlling for effects of sleep treatments. Compared to sea level, subjects reported higher levels of confusion (p < 0.01) and performed worse on the TMT A (p < 0.05) and the emotion recognition test (p < 0.05) on nights when they received no treatment at high altitude. These results suggest that stabilizing breathing (ASV) or increasing oxygenation (supplemental oxygen) during sleep can reduce feelings of fatigue and confusion, but that daytime hypoxia may play a larger role in other cognitive impairments reported at high altitude. Furthermore, this study provides evidence that some aspects of cognition (executive control, risk inhibition, sustained attention) improve with acclimatization

Low-Cost One-Step Fabrication of Highly Conductive ZnO:Cl Transparent Thin Films with Tunable Photocatalytic Properties via Aerosol-Assisted Chemical Vapor Deposition

Low-cost, high-efficiency, and high quality Cl-doped ZnO (ZnO:Cl) thin films that can simultaneously function as transparent conducting oxides (TCOs) and photocatalysts are described. The films have been fabricated by a facile and inexpensive solution-source aerosol-assisted chemical vapor deposition technique using NH4Cl as an effective, cheap, and abundant source of Cl. Successful ClO substitutional doping in the ZnO films was evident from powder X-ray diffraction, X-ray photoelectron spectroscopy, and time-of-flight secondary ion mass spectrometry results, while scanning electron microscopy reveals the impact of Cl doping on the ZnO thin film morphology. All ZnO:Cl films deposited were transparent and uncolored; optical transmittance in the visible region (400−700 nm) exceeded 80% for depositions using 5−20 mol % Cl. Optimal electrical properties were achieved when using 5 mol % Cl with a minimum measured resistivity of (2.72 ± 0.04) × 10−3 Ω·cm, in which the charge carrier concentration and mobility were measured at (8.58 ± 0.16) × 1019 cm−3 and 26.7 ± 0.1 cm2 V−1 s −1 respectively, corresponding to a sheet resistance (Rsh) of 41.9 Ω□−1 at a thickness of 650 nm. In addition to transparent conducting properties, photocatalytic behavior of stearic acid degradation in the ZnO:Cl films was also observed with an optimal Cl concentration of 7 mol % Cl, with the highest formal quantum efficiency (ξ) measured at (1.63 ± 0.03) × 10−4 molecule/photon, while retaining a visible transparency of 80% and resistivity ρ = (9.23 ± 0.13) × 10−3 Ω·cm. The dual functionality of ZnO:Cl as both a transparent conductor and an efficient photocatalyst is a unique combination of properties making this a particularly unusual material

Contemporary Surgery for Obstructive Sleep Apnea Syndrome

Surgical treatment of obstructive sleep apnea syndrome (OSAS) has been available in some form for greater than three decades. Early management for airway obstruction during sleep relied on tracheotomy which although life saving was not well accepted by patients. In the early eighties two new forms of treatment for OSAS were developed. Surgically a technique described as a uvulopalatopharyngoplasty (UPPP) was used to treat the retropalatal region for snoring and sleep apnea. Concurrently sleep medicine developed a nasal continuous positive airway pressure (CPAP) device to manage nocturnal airway obstruction. Both of these measures were used to expand and stabilize the pharyngeal airway space during sleep. The goal for each technique was to limit or alleviate OSAS. Almost 30 yr later these two treatment modalities continue to be the mainstay of contemporary treatment. As expected, CPAP device technology improved over time along with durable goods. Surgery followed suit and additional techniques were developed to treat soft and bony structures of the entire upper airway (nose, palate and tongue base). This review will only focus on the contemporary surgical methods that have demonstrated relatively consistent positive clinical outcomes. Not all surgical and medical treatment modalities are successful or even partially successful for every patient. Advances in the treatment of OSAS are hindered by the fact that the primary etiology is still unknown. However, both medicine and surgery continue to improve diagnostic and treatment methods. Methods of diagnosis as well as treatment regimens should always include both medical and surgical collaborations so the health and quality of life of our patients can best be served

An empirical Bayes approach to incorporating demand intermittency and irregularity into inventory control

Article asserts that spare parts inventory management is complex due to the combined impact of intermittent and variable demand patterns. This study proposes a novel nonparametric Bayesian forecasting approach with its roots in the empirical Bayes paradigm

Carbon cycling in Lake Superior

Carbon (C) cycling in Lake Superior was studied within the Keweenaw Interdisciplinary Transport Experiment in Superior (KITES) project to assess (1) whether the lake is net heterotrophic, (2) sources, sinks and residence time for dissolved organic carbon (DOC), (3) importance of terrigenous organic C subsidies, and (4) factors limiting C flow through bacteria. During 3 years of fieldwork, measurements were made of spatial and temporal distributions of C pools and rates of photosynthesis, community respiration, and bacterial production. Measurements were made of the composition of dissolved organic matter (DOM), rates of DOM photolysis, lability of DOM toward microbial consumption, and river inputs of DOM. All measurements suggest the lake is net heterotrophic. The C:N ratios of DOM suggest that it is primarily of terrigenous origin, but other characteristics (size distribution, UV absorption) point to the presence of autochthonous DOM and to alteration of terrigenous material. The lake mass balance indicates that the residence time (∼8 years) of the DOC pool (17 Tg) is short relative to the hydrologic residence time (170 years). The known flux of terrigenous DOC (∼1 Tg/yr) is too low to support annual bacterial carbon demand (6–38 Tg/yr), but microbial respiration is the major sink for terrigenous DOC. A rapidly cycling, autochthonous DOC pool must exist. Microbial activity was correlated with temperature, phosphorus availability, and DOC concentration but not with photosynthesis rates. Measurements of respiration (∼40 Tg/yr), photosynthesis (2–7 Tg/yr), and bacterial production (0.5–2 Tg/yr) are not all mutually compatible and result in a discrepancy in the organic carbon budget

β-diversity in temperate grasslands is driven by stronger environmental filtering of plant species with large genomes

Elucidating mechanisms underlying community assembly and biodiversity patterns is central to ecology and evolution. Genome size (GS) has long been hypothesized to potentially affect species' capacity to tolerate environmental stress and might therefore help drive community assembly. However, its role in driving β-diversity (i.e., spatial variability in species composition) remains unclear. We measured GS for 161 plant species and community composition across 52 sites spanning a 3200-km transect in the temperate grasslands of China. By correlating the turnover of species composition with environmental dissimilarity, we found that resource filtering (i.e., environmental dissimilarity that includes precipitation, and soil nitrogen and phosphorus concentrations) affected β-diversity patterns of large-GS species more than small-GS species. By contrast, geographical distance explained more variation of β-diversity for small-GS than for large-GS species. In a 10-year experiment manipulating levels of water, nitrogen, and phosphorus, adding resources increased plant biomass in species with large GS, suggesting that large-GS species are more sensitive to the changes in resource availability. These findings highlight the role of GS in driving community assembly and predicting species responses to global change

Financing Maternal and Child Health—What Are the Limitations in Estimating Donor Flows and Resource Needs?

Marco Schäferhoff and colleagues critique funding estimates for the maternal and child health Millennium Development Goals, and make recommendations for improving the tracking of financing flows and estimating the costs of scaling up interventions for mothers and children

Treatment With an Angiopoietin-1 Mimetic Peptide Improves Cognitive Outcome in Rats With Vascular Dementia

BACKGROUND AND PURPOSE: Vascular dementia (VaD) is a complex neurodegenerative disease affecting cognition and memory. There is a lack of approved pharmacological treatments specifically for VaD. In this study, we investigate the therapeutic effects of AV-001, a Tie2 receptor agonist, in middle-aged rats subjected to a multiple microinfarct (MMI) model of VaD. METHODS: Male, 10-12 month-old, Wistar rats were employed. The following experimental groups were used: Sham, MMI, MMI+1 μg/Kg AV-001, MMI+3 μg/Kg AV-001, MMI+6 μg/Kg AV-001. AV-001 treatment was initiated at 1 day after MMI and administered once daily via intraperitoneal injection. An investigator blinded to the experimental groups conducted a battery of neuro-cognitive tests including modified neurological severity score (mNSS) test, novel object recognition test, novel odor recognition test, three chamber social interaction test, and Morris water maze test. Rats were sacrificed at 6 weeks after MMI. RESULTS: There was no mortality observed after 1, 3, or 6 μg/Kg AV-001 treatment in middle-aged rats subjected to MMI. AV-001 treatment (1, 3, or 6 μg/Kg) does not significantly alter blood pressure or heart rate at 6 weeks after MMI compared to baseline values or the MMI control group. Treatment of MMI with 1 or 3 μg/Kg AV-001 treatment does not significantly alter body weight compared to Sham or MMI control group. While 6 μg/Kg AV-001 treated group exhibit significantly lower body weight compared to Sham and MMI control group, the weight loss is evident starting at 1 day after MMI when treatment was initiated and is not significantly different compared to its baseline values at day 0 or day 1 after MMI. AV-001 treatment significantly decreases serum alanine aminotransferase, serum creatinine, and serum troponin I levels compared to the MMI control group; however, all values are within normal range. MMI induces mild neurological deficits in middle-aged rats indicated by low mNSS scores (\u3c6 on a scale of 0-18). Compared to control MMI group, 1 μg/Kg AV-001 treatment group did not exhibit significantly different mNSS scores, while 3 and 6 μg/Kg AV-001 treatment induced significantly worse mNSS scores on days 21-42 and 14-42 after MMI, respectively. MMI in middle-aged rats induces significant cognitive impairment including short-term memory loss, long-term memory loss, reduced preference for social novelty and impaired spatial learning and memory compared to sham control rats. Rats treated with 1 μg/Kg AV-001 exhibit significantly improved short-term and long-term memory, increased preference for social novelty, and improved spatial learning and memory compared to MMI rats. Treatment with 3 μg/Kg AV-001 improves short-term memory and preference for social novelty but does not improve long-term memory or spatial learning and memory compared to MMI rats. Treatment with 6 μg/Kg AV-001 improves only long-term memory compared to MMI rats. Thus, 1 μg/Kg AV-001 treatment was selected as an optimal dose. Treatment of middle-aged rats subjected to MMI with 1 μg/Kg AV-001 significantly increases axon density, myelin density and myelin thickness in the corpus callosum, as well as increases synaptic protein expression, neuronal branching and dendritic spine density in the cortex, oligodendrocytes and oligodendrocyte progenitor cell number in the cortex and striatum and promotes neurogenesis in the subventricular zone compared to control MMI rats. CONCLUSIONS: In this study, we present AV-001 as a novel therapeutic agent to improve cognitive function and reduce white matter injury in middle aged-rats subjected to a MMI model of VaD. Treatment of MMI with 1 μg/Kg AV-001 significantly improves cognitive function, and increases axon density, remyelination and neuroplasticity in the brain of middle-aged rats