Ferritin nanovehicle for targeted delivery of cytochrome C to cancer cells

In this work, we have exploited the unique properties of a chimeric archaeal-human ferritin to encapsulate, deliver and release cytochrome c and induce apoptosis in a myeloid leukemia cell line. The chimeric protein combines the versatility in 24-meric assembly and cargo incorporation capability of Archaeglobus fulgidus ferritin with specific binding of human H ferritin to CD71, the “heavy duty” carrier responsible for transferrin-iron uptake. Delivery of ferritin-encapsulated cytochrome C to the Acute Promyelocytic Leukemia (APL) NB4 cell line, highly resistant to transfection by conventional methods, was successfully achieved in vitro. The effective liberation of cytochrome C within the cytosolic environment, demonstrated by double fluorescent labelling, induced apoptosis in the cancer cells

High School Student Athletes and Nonathletes\u27 Disciplinary Referrals and Grade Point Averages

High School Student Athletes and Nonathletes\u27 Disciplinary Referrals and Grade Point Averages by Jack Calhoun MEd, Georgia Southwestern State University, 1998 BS, Georgia Southwestern State University, 1997 Doctoral Study Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Education Walden University December 2014 This quantitative study investigated how athletic participation in public high schools influenced students\u27 academic achievement and positive social behavior. Disciplinary referrals are on the rise in American schools and are a cause of concern for teachers, administrators, parents, and community members. School personnel currently implement programs designed to curb discipline problems in the classroom and foster productive behavior among adolescents. There is some debate and conflicting literature on whether sports participation has a beneficial influence on students. The writings of Virgina Chomitz, who hypothesized a positive relationship between academic achievement and physical fitness, guided this research. This study analyzed grade point average (GPA) and discipline referral data for 4,433 students in a suburban American high school over a 3-year time period. The GPA and referral data for athletes and nonathletes were compared using multiple t tests, and it was found that athletes had significantly higher GPAs and lower discipline referrals when compared to nonathletes. These results, which match the original hypotheses, provide greater insight into how participating in athletics may improve a student\u27s behavior and academic achievement. With this knowledge, educators may place greater emphasis on athletics as a method to promote achievement and positive experiences among high school students. These positive effects will contribute to social change for students at an individual level and for entire school environments

Bacteriology of sputum in cystic fibrosis: evaluation of dithiothreitol as a mucolytic agent.

Liquefaction and homogenization have been recommended to ensure accurate, representative sputum cultures. We evaluated dithiothreitol (DTT) as mucolytic agent for culturing sputum samples obtained from 79 cystic fibrosis (CF) patients. Liquefaction with DTT was not superior to direct plating of specimens for routine qualitative cultures. Unliquefied sputum cultures failed to direct 3 of 47 Pseudomonas aeruginosa isolates; DTT-treated specimens missed 5 of 13 Candida albicans isolates. Neither treated nor untreated sputum cultures were completely successful in detecting Staphylococcus aureus or Enterobacteriaceae. Since Haemophilus influenzae was recovered from only two qualitative cultures, we could not evaluate the effect of DTT on the receovery of this organism. However, 27 of 29 strains of H. influenzae were inhibited by concentrations of DTT near the recommended final working concentration of 50 micrograms/ml, suggesting that liquefaction might impair isolation of this organism. Liquefaction with DTT permitted quantitative cultures of CF sputum. The predominant pathogen in our CF population was P. aeruginosa; 37 of 43 (86%) patients were colonized with this organism. Median densities of rough and mucoid strains were 3.2 x 10(7) and 4.3 x 10(7) colony-forming units per ml, respectively. Previous oral antistaphylococcal therapy may have accounted for the observed low density of S. aureus (mean density, 3.5 x 10(3) colony-forming units per ml). We conclude that DTT treatment does not improve recovery of organisms from qualitative cultures but does facilitate quantitative studies of S. aureus and P. aeruginosa in CF sputum.VoRSUNY DownstatePediatricsN/

A Solanum lycopersicum polyamine oxidase contributes to the control of plant growth, xylem differentiation, and drought stress tolerance

Polyamines are involved in several plant physiological processes. In Arabidopsis thaliana, five FAD-dependent polyamine oxidases (AtPAO1 to AtPAO5) contribute to polyamine homeostasis. AtPAO5 catalyzes the back-conversion of thermospermine (T-Spm) to spermidine and plays a role in plant development, xylem differentiation, and abiotic stress tolerance. In the present study, to verify whether T-Spm metabolism can be exploited as a new route to improve stress tolerance in crops and to investigate the underlying mechanisms, tomato (Solanum lycopersicum) AtPAO5 homologs were identified (SlPAO2, SlPAO3, and SlPAO4) and CRISPR/Cas9-mediated loss-of-function slpao3 mutants were obtained. Morphological, molecular, and physiological analyses showed that slpao3 mutants display increased T-Spm levels and exhibit changes in growth parameters, number and size of xylem elements, and expression levels of auxin- and gibberellin-related genes compared to wild-type plants. The slpao3 mutants are also characterized by improved tolerance to drought stress, which can be attributed to a diminished xylem hydraulic conductivity that limits water loss, as well as to a reduced vulnerability to embolism. Altogether, this study evidences conservation, though with some significant variations, of the T-Spm-mediated regulatory mechanisms controlling plant growth and differentiation across different plant species and highlights the T-Spm role in improving stress tolerance while not constraining growth

Polyamine metabolism dysregulation contributes to muscle fiber vulnerability in ALS

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive paralysis due to motor neuron degeneration with no curative therapy despite extensive biomedical research. One of the primary targets of ALS is skeletal muscle, which undergoes profound functional changes as the disease progresses. To better understand how altered innervation interferes with muscle homeostasis during disease progression, we generated a spatial transcriptomics dataset of skeletal muscle in the SOD1G93A mouse model of ALS. Using this strategy, we identified polyamine metabolism as one of the main altered pathways in affected muscle fibers. By establishing a correlation between the vulnerability of muscle fibers and the dysregulation of this metabolic pathway, we show that disrupting polyamine homeostasis causes impairments similar to those seen in ALS muscle. Finally, we show that restoration of polyamine homeostasis rescues the muscle phenotype in SOD1G93A mice, opening new perspectives for the treatment of ALS

Off-target inhibition of human dihydroorotate dehydrogenase (hDHODH) highlights challenges in the development of fat mass and obesity-associated protein (FTO) inhibitors

FTO, an N6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) RNA demethylase, is a promising target for treating acute myeloid leukemia (AML) due to the significant anticancer activity of its inhibitors in preclinical models. Here, we demonstrate that the FTO inhibitor FB23-2 suppresses proliferation across both AML and CML cell lines, irrespective of FTO dependency, indicating an alternative mechanism of action. Metabolomic analysis revealed that FB23-2 induces the accumulation of dihydroorotate (DHO), a key intermediate in pyrimidine nucleotide synthesis catalyzed by human dihydroorotate dehydrogenase (hDHODH). Notably, structural similarities between the catalytic pockets of FTO and hDHODH enabled FB23-2 to inhibit both enzymes. In contrast, the hDHODH-inactive FB23-2 analog, ZLD115, required FTO for its antiproliferative activity. Similarly, the FTO inhibitor CS2 (brequinar), known as one of the most potent hDHODH inhibitors, exhibited FTO-independent antileukemic effects. Uridine supplementation fully rescued leukemia cells from FB23-2 and CS2-induced growth inhibition, but not ZLD115, confirming the inhibition of pyrimidine synthesis as the primary mechanism of action underlying their antileukemic activity. These findings underscore the importance of considering off-target effects on hDHODH in the development of FTO inhibitors to optimize their therapeutic potential and minimize unintended consequences

A dynamic load balancing algorithm for Quality of Service and mobility management in next generation home networks

Heterogeneity of connection technologies and nodes mobility open new challenges in home networks control strategies. Moreover, user's needs are changing towards applications requiring high transmission speeds such as 3D gaming, enhanced interactivity and high definition video. Each of those applications puts several constraints on the network capabilities to guarantee requirements on the Quality of Service. In this paper we introduce an innovative concept based on fast load balancing algorithm operating on top of a convergence layer, in order to rapidly react to network changes and contemporaneously to satisfy strict application demands. We formulated the load balancing problem as a Multi-Commodity Flow and resolved it with a column generation approach using Lagrangian Relaxation and Dijkstra algorithm. The load balancing problem computational complexity is decreased with respect to state of the art load balancing solutions based on linear programming techniques. Proof of concept simulation results are reported