Hypercomplex quantum mechanics

The fundamental axioms of the quantum theory do not explicitly identify the algebraic structure of the linear space for which orthogonal subspaces correspond to the propositions (equivalence classes of physical questions). The projective geometry of the weakly modular orthocomplemented lattice of propositions may be imbedded in a complex Hilbert space; this is the structure which has traditionally been used. This paper reviews some work which has been devoted to generalizing the target space of this imbedding to Hilbert modules of a more general type. In particular, detailed discussion is given of the simplest generalization of the complex Hilbert space, that of the quaternion Hilbert module.Comment: Plain Tex, 11 page

The Antioxidant Potential of the Mediterranean Diet in Patients at High Cardiovascular Risk: An In-Depth Review of the PREDIMED

Cardiovascular disease (CVD) is the leading global cause of death. Diet is known to be important in the prevention of CVD. The PREDIMED trial tested a relatively low-fat diet versus a high-fat Mediterranean diet (MedDiet) for the primary prevention of CVD. The resulting reduction of the CV composite outcome resulted in a paradigm shift in CV nutrition. Though many dietary factors likely contributed to this effect, this review focuses on the influence of the MedDiet on endogenous antioxidant systems and the effect of dietary polyphenols. Subgroup analysis of the PREDIMED trial revealed increased endogenous antioxidant and decreased pro-oxidant activity in the MedDiet groups. Moreover, higher polyphenol intake was associated with lower incidence of the primary outcome, overall mortality, blood pressure, inflammatory biomarkers, onset of new-onset type 2 diabetes mellitus (T2DM), and obesity. This suggests that polyphenols likely contributed to the lower incidence of the primary event in the MedDiet groups. In this article, we summarize the potential benefits of polyphenols found in the MedDiet, specifically the PREDIMED cohort. We also discuss the need for further research to confirm and expand the findings of the PREDIMED in a non-Mediterranean population and to determine the exact mechanisms of action of polyphenols

Pharmacological screening using an FXN-EGFP cellular genomic reporter assay for the therapy of Friedreich ataxia

Copyright @ 2013 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Friedreich ataxia (FRDA) is an autosomal recessive disorder characterized by neurodegeneration and cardiomyopathy. The presence of a GAA trinucleotide repeat expansion in the first intron of the FXN gene results in the inhibition of gene expression and an insufficiency of the mitochondrial protein frataxin. There is a correlation between expansion length, the amount of residual frataxin and the severity of disease. As the coding sequence is unaltered, pharmacological up-regulation of FXN expression may restore frataxin to therapeutic levels. To facilitate screening of compounds that modulate FXN expression in a physiologically relevant manner, we established a cellular genomic reporter assay consisting of a stable human cell line containing an FXN-EGFP fusion construct, in which the EGFP gene is fused in-frame with the entire normal human FXN gene present on a BAC clone. The cell line was used to establish a fluorometric cellular assay for use in high throughput screening (HTS) procedures. A small chemical library containing FDA-approved compounds and natural extracts was screened and analyzed. Compound hits identified by HTS were further evaluated by flow cytometry in the cellular genomic reporter assay. The effects on FXN mRNA and frataxin protein levels were measured in lymphoblast and fibroblast cell lines derived from individuals with FRDA and in a humanized GAA repeat expansion mouse model of FRDA. Compounds that were established to increase FXN gene expression and frataxin levels included several anti-cancer agents, the iron-chelator deferiprone and the phytoalexin resveratrol.Muscular Dystrophy Association (USA), the National Health and Medical Research Council (Australia), the Friedreich’s Ataxia Research Alliance (USA), the Brockhoff Foundation (Australia), the Friedreich Ataxia Research Association (Australasia), Seek A Miracle (USA) and the Victorian Government’s Operational Infrastructure Support Program

Dosimetrische und planungstechnische Untersuchungen der TomoTherapy (Accuray)

Die TomoTherapy bietet eine einzigartige Möglichkeit der intensitäts- modulierten Strahlentherapie. Ein schlitzartiger hochenergetischer, ionisierender Photonenstrahl wird durch einen binären Multi-Lamellen- Kollimator geformt und eine Vielzahl solcher Projektionen aus verschiedenen Einstrahlwinkeln auf ein Zielgebiet kumuliert. Durch diese Technik wird eine homogene Dosisverteilung im Zielgebiet, zumeist Tumorgewebe, mit steilen Gradienten zum Normalgewebe erreicht. Die Vorzüge der einzigartigen Bestrahlungstechnik der TomoTherapy wurden kombiniert, um eine neue Methode der robusten Ganzkörperbestrahlung zu entwickeln und in die klinische Routine zu implementieren. Von nationalen und internationalen Dosimetrieprotokollen vorgeschriebene Referenzbedingungen für die Absolutdosimetrie sind mit dem Bestrahlungsgerät TomoTherapyHD unter mehreren Aspekten nicht zu erreichen. Mittels Monte Carlo Simulationen werden Fragestellungen beantwortet, die Unsicherheiten der Absolutdosimetrie reduzieren. Die Unsicherheiten der Dosimetrie kleiner Felder werden in vielen Publikationen untersucht. In dieser Arbeit wird erstmalig eine fluenzgewichtete Subfeldgröße eines helikalen TomoTherapy Planes definiert. Dieser Parameter bietet die Möglichkeit einer Beschreibung der Komplexität eines Bestrahlungsplanes und ist eine Größe, um Genauigkeiten von Messsystemen für die Patientenqualitätssicherungen in der klinischen Dosimetrie zu verifizieren. In der vorliegenden kumulativen Dissertation werden Hintergründe zu den beschriebenen Sachverhalten beschrieben und die entsprechenden Ergebnisse vorgestellt. Mit dieser Arbeit wird ein Beitrag geleistet, die Qualitätssicherung der Strahlentherapie weiter zu verbessern und Ungenauigkeiten in der klinischen Dosimetrie zu minimieren

Utilizing small nutrient compounds as enhancers of exercise-induced mitochondrial biogenesis.

Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has been given to understanding the molecular cues stimulated by endurance exercise that culminate in this adaptive response. In turn, this research has led to the identification of pharmaceutical compounds and small nutritional bioactive ingredients that appear able to amplify exercise-responsive signaling pathways in skeletal muscle. The aim of this review is to discuss these purported exercise mimetics and bioactive ingredients in the context of mitochondrial biogenesis in skeletal muscle. We will examine proposed modes of action, discuss evidence of application in skeletal muscle in vivo and finally comment on the feasibility of such approaches to support endurance-training applications in humans

Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu[superscript 230], located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.Glenn Foundation for Medical ResearchEllison Medical FoundationJuvenile Diabetes Research Foundation InternationalUnited Mitochondrial Disease FoundationNational Institutes of Health (U.S.)National Institute of Allergy and Infectious Diseases (U.S.

The Nature of meta-Tyrosine Toxicity to Phenylalanyl-tRNA Synthetase Editing-Defective Escherichia coli

Faithful translation of the genetic code into amino acid sequences is important for the viability of organisms. One source of error in translation is the mischarging of tRNAs with the incorrect amino acid due to structural similarities between the cognate and non-cognate amino acids. If gone unchecked, these mischarged tRNAs would provide an amino acid to the ribosome that does not match its codon, thereby causing mistranslation of the mRNA sequence. The proteins that are responsible for charging tRNAs with the correct amino acids are called aminoacyl-tRNA synthetases (aaRS). Some of these aaRSs have evolved an editing mechanism that allows them to cleave off a non-cognate amino acid from the mischarged tRNA, which is broadly conserved across all domains of life. This editing activity seems like it would be essential for life, however there are many examples of organisms who have lost their editing function to no ill effect. Moreover, there are examples of organisms that have conserved their editing function, but do not show a growth defect when it is eliminated, such as E. coli and its phenylalanine aaRS (PheRS). We chose to study E. coli’s PheRS to understand why its editing function is evolutionarily conserved. We discovered that the non-protein amino acid meta-Tyrosine (m-Tyr) is toxic to PheRS editing-defective (PheRS edit-) E. coli. We then sought to understand why m-Tyr is so toxic to PheRS edit- cells. We used chemical mutagenesis to find m-Tyr resistant mutants and then performed whole genome sequencing to find mutated genes that could contribute to the resistance. We found that mutations in uptake and efflux transport could provide resistance by keeping or getting m-Tyr out of the cell. We also identified a resistance mutation that likely elevated Phe production, which provided resistance by most likely increasing competitive inhibition of the m-Tyr. We also observed PheRS edit- E. coli after m-Tyr exposure directly via light and electron microscopy. We observed large protein aggregates forming in the cells, which indicated that the m-Tyr destabilized a large fraction of the proteome. We also performed transcriptomic analysis of PheRS edit- E. coli after m-Tyr exposure to see what stress responses they used to deal with m-Tyr toxicity. We found a strong induction of the unfolded protein stress response, as well as oxidative stress, DNA damage stress, and indications of lost ion homeostasis. Based on these findings, we proposed a model of m-Tyr toxicity that involves a cascading and self-reinforcing chain reaction of cellular stresses that ultimately leads to cell death

SIRT1 regulates the neurogenic potential of neural precursors in the adult subventricular zone and hippocampus

Within the two neurogenic niches of the adult mammalian brain, i.e., the subventricular zone lining the lateral ventricle and the subgranular zone of the hippocampus, there exist distinct populations of proliferating neural precursor cells that differentiate to generate new neurons. Numerous studies have suggested that epigenetic regulation by histone-modifying proteins is important in guiding precursor differentiation during development; however, the role of these proteins in regulating neural precursor activity in the adult neurogenic niches remains poorly understood. Here we examine the role of an NAD+-dependent histone deacetylase, SIRT1, in modulating the neurogenic potential of neural precursors in the neurogenic niches of the adult mouse brain. We show that SIRT1 is expressed by proliferating adult subventricular zone and hippocampal neural precursors, although its transcript and protein levels are dramatically reduced during neural precursor differentiation. Utilizing a lentiviral-mediated delivery strategy, we demonstrate that abrogation of SIRT1 signaling by RNAi does not affect neural precursor numbers or their proliferation. However, SIRT1 knock down results in a significant increase in neuronal production in both the subventricular zone and the hippocampus. In contrast, enhancing SIRT1 signaling either through lentiviral-mediated SIRT1 overexpression or through use of the SIRT1 chemical activator Resveratrol prevents adult neural precursors from differentiating into neurons. Importantly, knock down of SIRT1 in hippocampal precursors in vivo, either through RNAi or through genetic ablation, promotes their neurogenic potential. These findings highlight SIRT1 signaling as a negative regulator of neuronal differentiation of adult subventricular zone and hippocampal neural precursors

Meanings of Community: Educational Developers Experience Care, Satisfying Contributions, and Belonging in a Collaboration across Institutions

We share insights from a mixed methods study to describe the experience of educational developers participating in a community of practice (CoP). This CoP consisted of 19 leaders at eight institutions, serving collectively as facilitators of a hybrid, across-institutional, seven-week workshop series on course design for graduate students and postdoctoral scholars. From results of a survey examining the functional and sustaining features of the community, we illustrate that members experience the community aspect of our CoP primarily as a sense of satisfaction/personal fulfillment and, to an extent, in the effectiveness/productiveness of collaborations between members. Members of our CoP experience several community-related benefits specific to their across-institution collaborations. We demonstrate the importance of members’ sense of belonging, overall professional development, and well-being for sustaining our CoP

The Sirtuin Family Members SIRT1, SIRT3 and SIRT6: Their Role In Vascular Biology and Atherogenesis

The sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. Activation of SIRTs appears to have beneficial effects on lipid metabolism and antioxidants, prompting investigation of the roles of these proteins in atherogenesis. Although clinical data are currently limited, the availability and safety of SIRT activators such as metformin and resveratrol provide an excellent opportunity to conduct research to better understand the role of SIRTs in human atherosclerosis. Encouraging observations from preclinical studies necessitate rigorous large, prospective, randomized clinical trials to determine the roles of SIRT activators on the progression of atherosclerosis and ultimately on cardiac outcomes, such as myocardial infarction and mortality