Inflammatory and Glutamatergic Homeostasis Are Involved in Successful Aging

Whole body studies using long-lived growth hormone receptor gene disrupted or knock out (GHR-KO) mice report global GH resistance, increased insulin sensitivity, reduced insulin-like growth factor 1 (IGF-1), and cognitive retention in old-age, however, little is known about the neurobiological status of these mice. The aim of this study was to determine if glutamatergic and inflammatory markers that are altered in aging and/or age-related diseases and disorders, are preserved in mice that experience increased healthspan. We examined messenger ribonucleic acid (mRNA) expression levels in the brain of 4- to 6-, 8- to 10-, and 20- to 22-month GHR-KO and normal aging control mice. In the hippocampus, glutamate transporter 1 (GLT-1) and anti-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB)-p50 were elevated in 8- to 10-month GHR-KO mice compared with age-matched controls. In the hypothalamus, NFκB-p50, NFκB-p65, IGF-1 receptor (IGF-1R), glutamate/aspartate transporter (GLAST), and 2-amino-3-(5-methyl-3-oxo 2,3-dihydro-1,2 oxazol-4-yl) propanoic acid receptor subunit 1 (GluA1) were elevated in 8- to 10- and/or 20- to 22-month GHR-KO mice when comparing genotypes. Finally, interleukin 1-beta (IL-1β) mRNA was reduced in 4- to 6- and/or 8- to 10-month GHR-KO mice compared with normal littermates in all brain areas examined. These data support the importance of decreased brain inflammation in early adulthood and maintained homeostasis of the glutamatergic and inflammatory systems in extended longevity

Coaxing HIS Data from Mandli Pavement Scans

The Kentucky Transportation Cabinet (KYTC) Division of Planning’s Highway Information Systems (HIS) database provides geometric information about horizontal and vertical curves, but its accuracy is unknown. An updated method of pavement analysis collects data by scanning the pavement as a van equipped with Mandli software drives the area of interest. The scans provide detailed information that can be used to calculate roadway geometry characteristics (e.g., curve radius, cross slope/superelevation, and grade). This study evaluated the ability of the Mandli data to support curve advisory calculations and find a way to utilize Mandli data to improve the existing HIS database. To this end, the report includes a literature review to determine applicability of data, a series of data validation steps to define Mandli’s accuracy, and an evaluation of tools that convert Mandli into usable HIS data. The data attributes of focus are horizontal curve radius, grade, and cross slope. Horizontal curve radii values were evaluated using University of Nevada Reno’s ArcMAP plugin, Florida DOT’s curvature extension tool, and the University of Kentucky’s Curvature Automatic Tool (UKCAT). These tools were tested for usability, efficiency, and accuracy. Vertical curve attributes, including grade and cross slope, were evaluated by comparing Mandli data to manual field measurements, design plans, and other data collection methods. After data collection and analysis, researchers outline a newly developed method for converting Mandli data into a usable form and implementing it in HIS

Adsorption of DNA Oligonucleotides by Titanium Dioxide Nanoparticles

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Langmuir, copyright © American Chemical Society after peer review and technical editing by publisher. To access the final edited and published work see http://dx.doi.org/10.1021/la404633pTitanium dioxide (TiO2) or titania shows great promise in detoxification and drug delivery. To reach its full potential, it is important to interface TiO2 with biomolecules to harness their molecular recognition function. To this end, DNA attachment is an important topic. Previous work has mainly focused on long double-stranded DNA or single nucleotides. For biosensor development and targeted drug delivery, it is more important to use single-stranded oligonucleotides. Herein, the interaction between fluorescently labeled oligonucleotides and TiO2 nanoparticles is reported. The point of zero charge (PZC) of TiO2 is around 6 in water or acetate buffer; therefore, the particles are positively charged at lower pH. However, if in phosphate or citrate buffer, the particles are negatively charged, even at pH ∼2, suggesting strong adsorption of buffer anions. DNA adsorption takes place mainly via the phosphate backbone, although the bases might also have moderate contributions. Peptide nucleic acids (PNAs) with an amide backbone cannot be adsorbed. DNA adsorption is strongly affected by inorganic anions, where phosphate and citrate can strongly inhibit DNA adsorption. DNA adsorption is promoted by adding salt or lowering pH. DNA adsorption is accompanied with fluorescence quenching, and double-stranded DNA showed reduced quenching, allowing for the detection of DNA using TiO2 nanoparticles.University of Waterloo || Canadian Foundation for Innovation || Natural Sciences and Engineering Research Council || Canadian Institutes of Health Research || Ontario Ministry of Research and Innovation |

Neutrophil extracellular traps in stored canine red blood cell units

BackgroundNeutrophil extracellular traps (NETs), webs of DNA and citrullinated histones extruded from activated neutrophils cause transfusion‐related acute lung injury. Supernatants of stored red blood cell (RBC) units might promote NETosis in neutrophils from the units or from transfusion recipients.Hypotheses(1) NETs form during storage of canine RBC, (2) leukoreduction (LR) before storage of RBC reduces NETosis, and (3) supernatant from stored, nonleukoreduced (NLR) RBC units induces NETosis in healthy canine neutrophils modeling transfusion recipients.AnimalsSix healthy purpose‐bred research dogs were utilized for blood donation.MethodsProspective controlled study. RBC units were collected from each dog, aseptically divided into 2 equal subunits, 1 of which was leukoreduced, and stored for 42 days. Stored units were sampled biweekly for quantification of NET markers citrullinated histone H3 (Western blot) and cell‐free DNA (cfDNA) (DNA dye binding). Unit supernatants were applied ex vivo to canine neutrophils and extracellular DNA release representing NETosis was assessed.ResultsMarkers of NETs increased during RBC storage (cfDNA P < .0001 and citrullinated H3 P = .0002) and were higher in NLR than LR units (day 42 LR cfDNA 0.34 ± 0.82 ng/mL vs day 42 NLR 1361.07 ± 741.00 ng/mL, P < .0001; day 42 LR citrullinated H3 0.19 ± 0.13 AU vs NLR 0.57 ± 0.34 AU, P = .007). Isolated neutrophils did not form NETs when exposed to stored canine RBC supernatant.Conclusions and Clinical ImportanceNETosis occurs in stored canine NLR RBC units, and is attenuated by LR before storage. NETs might be mediators of transfusion reactions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162806/3/jvim15876-sup-0001-supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162806/2/jvim15876_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162806/1/jvim15876.pd

Comparison of branded rugby headguards on their effectiveness in reducing impact on the head

Aim: To compare the available brands of rugby headguards and evaluate their impact attenuation properties at various locations on the cranium, with regard to concussion prevention.Methods: Seven different branded headguards were fitted onto a rigid headform and drop-tested in three different positions. An accelerometer measured the linear acceleration the headform experienced on impact with the ground. Each test involved dropping the headform from a height that generated 103.8 g on average when bare, which is the closest acceleration to the upper limit of the concussion threshold of 100 g. A mean peak acceleration for each drop position was calculated and compared with the bare baseline measurement.Results: Each headguard demonstrated a significant decrease in the mean peak acceleration from the baseline value (all p≤0.01). Overall the Canterbury Ventilator was the most effective headguard, decreasing the impact force on average by 47%. The least effective was the XBlades Elite headguard, averaging a force reduction of 27%. In five of the seven headguards, the right side of the headwear was the most effective at reducing impact force.Conclusion: Overall, the results indicate that it would be beneficial to wear a headguard during rugby in order to reduce the impact forces involved in head collisions. There was also a clear difference in performance between the tested brands, establishing the Canterbury headguard as the most effective. However, only one model of headguard from each brand was tested, so further research evaluating all other models should be considered.</p

Understanding the contribution of metabolism to Mycobacterium tuberculosis drug tolerance

Treatment o

Measurement of Physical Activity with Wrist-Worn ActiGraph GT3X+ in Older Women

International Journal of Exercise Science 15(7): 1538-1553, 2022. Higher wear compliance has been seen with wrist placed accelerometers versus hip placed. Performance of wrist placed ActiGraph GT3X+ accelerometer (GT3X+, ActiGraph LLC, Pensacola, FL) in assessing physical activity (PA) remains unclear. PURPOSE: This study examined GT3X+’s performance in measuring PA energy expenditure (PAEE) and classifying PA intensity in older women. METHODS: Women [n = 89, age = 65.6 (4.3)] wore GT3X+ and SenseWear Armband Mini (SWAM, BodyMedia Inc. Pittsburgh, PA) for 2 weeks. Concurrently, doubly labeled water (DLW) determined total daily energy expenditure (TDEE). Resting energy expenditure (REE) was determined by Indirect Calorimetry. Data was processed using manufacturer-provided software. Bivariate correlations, Intra Class Correlations, and Bland-Altman plots were performed to evaluate agreement between GT3X+ and criterion measures for sedentary time, light and moderate-to-vigorous PA (determined by SWAM) and PAEE (determined by SWAM and by DLW and REE). Epoch-by-epoch analysis evaluated discrepancy and agreement of PA intensity classification between GT3X+ and SWAM. RESULTS: For PAEE, GT3X+ showed moderate correlations with criterion measures (r = 0.413, 0.400 with SWAM; r = 0.564, 0.501 with DLW and REE), but Bland-Altman plots showed large variability. When estimating time spent in PA intensity, GT3X+ underestimated sedentary time and overestimated PA intensity compared to SWAM. During epoch-by-epoch analysis, GT3X+ misclassified light intensity PA as moderate-to-vigorous PA 72% of the time. Counts per minute showed strong correlations with criterion measures (r = 0.68, 0.625 for SWAM and DLW and REE respectively). CONCLUSION: Current equations and cut points do not provide accurate measures of PA with wrist-worn GT3X+ in older women

Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors

The synthetic steroid mifepristone blocks the growth of ovarian cancer cells, yet the mechanism driving such effect is not entirely understood. Unbiased genomic and proteomic screenings using ovarian cancer cell lines of different genetic backgrounds and sensitivities to platinum led to the identification of two key genes upregulated by mifepristone and involved in the unfolded protein response (UPR): the master chaperone of the endoplasmic reticulum (ER), glucose regulated protein (GRP) of 78 kDa, and the CCAAT/enhancer binding protein homologous transcription factor (CHOP). GRP78 and CHOP were upregulated by mifepristone in ovarian cancer cells regardless of p53 status and platinum sensitivity. Further studies revealed that the three UPR-associated pathways, PERK, IRE1α, and ATF6, were activated by mifepristone. Also, the synthetic steroid acutely increased mRNA translation rate, which, if prevented, abrogated the splicing of XBP1 mRNA, a non-translatable readout of IRE1α activation. Moreover, mifepristone increased LC3-II levels due to increased autophagic flux. When the autophagic–lysosomal pathway was inhibited with chloroquine, mifepristone was lethal to the cells. Lastly, doses of proteasome inhibitors that are inadequate to block the activity of the proteasomes, caused cell death when combined with mifepristone; this phenotype was accompanied by accumulation of poly-ubiquitinated proteins denoting proteasome inhibition. The stimulation by mifepristone of ER stress and autophagic flux offers a therapeutic opportunity for utilizing this compound to sensitize ovarian cancer cells to proteasome or lysosome inhibitors.Fil: Zhang, Lei. University Of South Dakota; Estados UnidosFil: Hapon, María Belén. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Goyeneche, Alicia A.. University Of South Dakota; Estados Unidos. McGill University; CanadáFil: Srinivasan, Rekha. University Of South Dakota; Estados UnidosFil: Gamarra Luques, Carlos Diego. University Of South Dakota; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Callegari, Eduardo A.. University Of South Dakota; Estados UnidosFil: Drappeau, Donis D.. University Of South Dakota; Estados UnidosFil: Terpstra, Erin J.. University Of South Dakota; Estados UnidosFil: Pan, Bo. University Of South Dakota; Estados UnidosFil: Knapp, Jennifer R.. University of Kansas; Estados UnidosFil: Chien, Jeremy. University of Kansas; Estados UnidosFil: Wang, Xuejun. University Of South Dakota; Estados UnidosFil: Eyster, Kathleen M.. University Of South Dakota; Estados UnidosFil: Telleria, Carlos Marcelo. University Of South Dakota; Estados Unidos. McGill University; Canadá. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Variational Deep Semantic Hashing for Text Documents

As the amount of textual data has been rapidly increasing over the past decade, efficient similarity search methods have become a crucial component of large-scale information retrieval systems. A popular strategy is to represent original data samples by compact binary codes through hashing. A spectrum of machine learning methods have been utilized, but they often lack expressiveness and flexibility in modeling to learn effective representations. The recent advances of deep learning in a wide range of applications has demonstrated its capability to learn robust and powerful feature representations for complex data. Especially, deep generative models naturally combine the expressiveness of probabilistic generative models with the high capacity of deep neural networks, which is very suitable for text modeling. However, little work has leveraged the recent progress in deep learning for text hashing. In this paper, we propose a series of novel deep document generative models for text hashing. The first proposed model is unsupervised while the second one is supervised by utilizing document labels/tags for hashing. The third model further considers document-specific factors that affect the generation of words. The probabilistic generative formulation of the proposed models provides a principled framework for model extension, uncertainty estimation, simulation, and interpretability. Based on variational inference and reparameterization, the proposed models can be interpreted as encoder-decoder deep neural networks and thus they are capable of learning complex nonlinear distributed representations of the original documents. We conduct a comprehensive set of experiments on four public testbeds. The experimental results have demonstrated the effectiveness of the proposed supervised learning models for text hashing.Comment: 11 pages, 4 figure

Alginate Composition Effects on a Neural Stem Cell-Seeded Scaffold

The purpose of this study was to evaluate the effects of alginate composition on the neurotrophic factor release, viability, and proliferation of encapsulated neural stem cells (NSCs), as well as on the mechanical stability of the scaffold itself. Four compositions were tested: a high guluronic acid (68%) and a high mannuronic acid (54%) content alginate, with or without a poly-L-lysine (PLL) coating layer. Enzyme-linked immunosorbent assay was used to quantify the release of brain-derived neurotrophic factor, glial-derived neurotrophic factor, and nerve growth factor from the encapsulated cells. All three factors were detected from encapsulated cells only when a high L-guluronic acid alginate without PLL was used. Additionally, capsules with this composition remained intact more frequently when exposed to solutions of low osmolarity, potentially indicating superior mechanical stability. Alginate beads with a PLL-coated, high D-mannuronic acid composition were the most prone to breakage in the osmotic pressure test, and were too fragile for histology and proliferation assays after 1 week in vitro. NSCs survived and proliferated in the three remaining alginate compositions similarly over the 21-day study course irrespective of scaffold condition. NSC-seeded alginate beads with a high L-guluronic acid, non-PLL-coated composition may be useful in the repair of injured nervous tissue, where the mechanism is the secretion of neuroprotective factors. We verify the neuroprotective effects of medium conditioned by NSC-seeded alginate beads on the serum withdrawal-mediated death of PC-12 cells here.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78133/1/ten.tec.2008.0302.pd