The Wooster Voice (Wooster, OH), 1949-12-08

Dr. T. Cuyler Young addresses the campus during the annual Wooster Day celebration. Dr. Delbert Lean will give his 40th annual reading of Charles Dickens\u27 Christmas Carol. Plans to build a darkroom for student publications are announced. Additionally, Wooster host the fall conference of the Ohio division of the National Student Association.https://openworks.wooster.edu/voice1941-1950/1204/thumbnail.jp

Elucidating the mechanism of ferrocytochrome c heme disruption by peroxidized cardiolipin

The interaction of peroxidized cardiolipin with ferrocytochrome c induces two kinetically and chemically distinct processes. The first is a rapid oxidation of ferrocytochrome c, followed by a slower, irreversible disruption of heme c. The oxidation of ferrocytochrome c by peroxidized cardiolipin is explained by a Fenton-type reaction. Heme scission is a consequence of the radical-mediated reactions initiated by the interaction of ferric heme iron with peroxidized cardiolipin. Simultaneously with the heme c disruption, generation of hydroxyl radical is detected by EPR spectroscopy using the spin trapping technique. The resulting apocytochrome c sediments as a heterogeneous mixture of high aggregates, as judged by sedimentation analysis. Both the oxidative process and the destructive process were suppressed by nonionic detergents and/or high ionic strength. The mechanism for generating radicals and heme rupture is presented

Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development

Producción CientíficaBackground: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.Asociación Española Contra el Cáncer (Proyecto AIOA110296BLAN).Gerencia Regional de Salud de Castilla y León (Proyecto GRS 726/A13

Complex I-Associated Hydrogen Peroxide Production Is Decreased and Electron Transport Chain Enzyme Activities Are Altered in n-3 Enriched fat-1 Mice

The polyunsaturated nature of n-3 fatty acids makes them prone to oxidative damage. However, it is not clear if n-3 fatty acids are simply a passive site for oxidative attack or if they also modulate mitochondrial reactive oxygen species (ROS) production. The present study used fat-1 transgenic mice, that are capable of synthesizing n-3 fatty acids, to investigate the influence of increases in n-3 fatty acids and resultant decreases in the n-6∶n-3 ratio on liver mitochondrial H2O2 production and electron transport chain (ETC) activity. There was an increase in n-3 fatty acids and a decrease in the n-6∶n-3 ratio in liver mitochondria from the fat-1 compared to control mice. This change was largely due to alterations in the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine, with only a small percentage of fatty acids in cardiolipin being altered in the fat-1 animals. The lipid changes in the fat-1 mice were associated with a decrease (p<0.05) in the activity of ETC complex I and increases (p<0.05) in the activities of complexes III and IV. Mitochondrial H2O2 production with either succinate or succinate/glutamate/malate substrates was also decreased (p<0.05) in the fat-1 mice. This change in H2O2 production was due to a decrease in ROS production from ETC complex I in the fat-1 animals. These results indicate that the fatty acid changes in fat-1 liver mitochondria may at least partially oppose oxidative stress by limiting ROS production from ETC complex I

The Susceptibility of Trypanosomatid Pathogens to PI3/mTOR Kinase Inhibitors Affords a New Opportunity for Drug Repurposing

In our study we describe the potency of established phosphoinositide-3-kinase (PI3K) and mammalian Target of Rapamycin (mTOR) kinase inhibitors against three trypanosomatid parasites: Trypanosoma brucei, T. cruzi, and Leishmania sp., which are the causative agents for African sleeping sickness, Chagas disease, and leishmaniases, respectively. We noted that these parasites and humans express similar kinase enzymes. Since these similar human targets have been pursued by the drug industry for many years in the discovery of cellular growth and proliferation inhibitors, compounds developed as human anti-cancer agents should also have effect on inhibiting growth and proliferation of the parasites. With that in mind, we selected eight established PI3K and mTOR inhibitors for profiling against these pathogens. Among these inhibitors is an advanced clinical candidate against cancer, NVP-BEZ235, which we demonstrate to be a highly potent trypanocide in parasite cultures, and in a mouse model of T. brucei infection. Additionally, we describe observations of these inhibitors' effects on parasite growth and other cellular characteristics

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut-brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.GB Rogers, DJ Keating, RL Young, M-L Wong, J Licinio, and S Wesseling

Abstract 2-F-PM4-1

In a typical sawmill, logs enter the mill and go through a de-barking process. Following this operation they go to the headrig where a sawyer moves the log repeatedly past a saw to remove boards one at a time. As more of the log interior is exposed with each board removed, the sawyer may re-orient the log periodically to cut from the best side. Sawn boards go through subsequent operations of edging and trimming, where defects near the edges and/or ends of the boards are removed to increase each board’s grade, and therefore its value. The cant (the cubical center section of the log) remaining from initial breakdown enters a resawing operation where additional boards are cut. These are also edged and trimmed