A New Class of Monoamine Oxidase Inhibitors

Newly synthesized compounds have been found to inhibit mitochondrial monoamine oxidase (MAO) in mouse brain and rat liver. A series of 2-acylamino-3- tert -aminopropiophenones acted preferentially against MAO type B (2-phenylethylamine as substrate), apparently irreversibly. 2-Decanoylamino-3-morpholinopropiophenone acted similarly in vivo toward the cerebral MAO, producing a dose-related inhibition. At high dose levels, MAO type A was also severely inhibited. The effects were produced rapidly and restoration of enzyme activity also appeared rapidly. The half-life for MAO type A could be estimated from the rate of enzyme reappearance to be 13 h. It is suggested that the amino ketones undergo a Β-elimination reaction at the enzyme's active site, forming a reactive species (an Α,Β-unsaturated ketone), which reacts covalently with a nucleophilic group of the enzyme by a Michael addition. Some other related compounds, derivatives of phenylpropane, also showed inhibitory activity against MAO, particularly against type A (serotonin as substrate). The morpholino compound might have promise as a quickly effective, short-acting inhibitor of MAO type B.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66333/1/j.1471-4159.1980.tb06611.x.pd

It is time to talk about people: a human-centered healthcare system

Examining vulnerabilities within our current healthcare system we propose borrowing two tools from the fields of engineering and design: a) Reason's system approach [1] and b) User-centered design [2,3]. Both approaches are human-centered in that they consider common patterns of human behavior when analyzing systems to identify problems and generate solutions. This paper examines these two human-centered approaches in the context of healthcare. We argue that maintaining a human-centered orientation in clinical care, research, training, and governance is critical to the evolution of an effective and sustainable healthcare system

How Do Human Cells React to the Absence of Mitochondrial DNA?

Mitochondrial biogenesis is under the control of two different genetic systems: the nuclear genome (nDNA) and the mitochondrial genome (mtDNA). The mtDNA is a circular genome of 16.6 kb encoding 13 of the approximately 90 subunits that form the respiratory chain, the remaining ones being encoded by the nDNA. Eukaryotic cells are able to monitor and respond to changes in mitochondrial function through alterations in nuclear gene expression, a phenomenon first defined in yeast and known as retrograde regulation. To investigate how the cellular transcriptome is modified in response to the absence of mtDNA, we used Affymetrix HG-U133A GeneChip arrays to study the gene expression profile of two human cell lines, 143BTK(-) and A549, which had been entirely depleted of mtDNA (rho(o) cells), and compared it with that of corresponding undepleted parental cells (rho(+) cells).Our data indicate that absence of mtDNA is associated with: i) a down-regulation of cell cycle control genes and a reduction of cell replication rate, ii) a down-regulation of nuclear-encoded subunits of complex III of the respiratory chain and iii) a down-regulation of a gene described as the human homolog of ELAC2 of E. coli, which encodes a protein that we show to also target to the mitochondrial compartment.Our results indicate a strong correlation between mitochondrial biogenesis and cell cycle control and suggest that some proteins could have a double role: for instance in controlling both cell cycle progression and mitochondrial functions. In addition, the finding that ELAC2 and maybe other transcripts that are located into mitochondria, are down-regulated in rho(o) cells, make them good candidates for human disorders associated with defective replication and expression of mtDNA

Horizons: nuclear astrophysics in the 2020s and beyond

Nuclear astrophysics is a field at the intersection of nuclear physics and astrophysics, which seeks to understand the nuclear engines of astronomical objects and the origin of the chemical elements. This white paper summarizes progress and status of the field, the new open questions that have emerged, and the tremendous scientific opportunities that have opened up with major advances in capabilities across an ever growing number of disciplines and subfields that need to be integrated. We take a holistic view of the field discussing the unique challenges and opportunities in nuclear astrophysics in regards to science, diversity, education, and the interdisciplinarity and breadth of the field. Clearly nuclear astrophysics is a dynamic field with a bright future that is entering a new era of discovery opportunities

Horizons: nuclear astrophysics in the 2020s and beyond

Nuclear astrophysics is a field at the intersection of nuclear physics and astrophysics, which seeks to understand the nuclear engines of astronomical objects and the origin of the chemical elements. This white paper summarizes progress and status of the field, the new open questions that have emerged, and the tremendous scientific opportunities that have opened up with major advances in capabilities across an ever growing number of disciplines and subfields that need to be integrated. We take a holistic view of the field discussing the unique challenges and opportunities in nuclear astrophysics in regards to science, diversity, education, and the interdisciplinarity and breadth of the field. Clearly nuclear astrophysics is a dynamic field with a bright future that is entering a new era of discovery opportunities

Horizons: Nuclear Astrophysics in the 2020s and Beyond

Nuclear Astrophysics is a field at the intersection of nuclear physics and astrophysics, which seeks to understand the nuclear engines of astronomical objects and the origin of the chemical elements. This white paper summarizes progress and status of the field, the new open questions that have emerged, and the tremendous scientific opportunities that have opened up with major advances in capabilities across an ever growing number of disciplines and subfields that need to be integrated. We take a holistic view of the field discussing the unique challenges and opportunities in nuclear astrophysics in regards to science, diversity, education, and the interdisciplinarity and breadth of the field. Clearly nuclear astrophysics is a dynamic field with a bright future that is entering a new era of discovery opportunities.Comment: 96 pages. Submitted to Journal of Physics

Astrophysical Origins of Ultrahigh Energy Cosmic Rays

In the first part of this review we discuss the basic observational features at the end of the cosmic ray energy spectrum. We also present there the main characteristics of each of the experiments involved in the detection of these particles. We then briefly discuss the status of the chemical composition and the distribution of arrival directions of cosmic rays. After that, we examine the energy losses during propagation, introducing the Greisen-Zaptsepin-Kuzmin (GZK) cutoff, and discuss the level of confidence with which each experiment have detected particles beyond the GZK energy limit. In the second part of the review, we discuss astrophysical environments able to accelerate particles up to such high energies, including active galactic nuclei, large scale galactic wind termination shocks, relativistic jets and hot-spots of Fanaroff-Riley radiogalaxies, pulsars, magnetars, quasar remnants, starbursts, colliding galaxies, and gamma ray burst fireballs. In the third part of the review we provide a brief summary of scenarios which try to explain the super-GZK events with the help of new physics beyond the standard model. In the last section, we give an overview on neutrino telescopes and existing limits on the energy spectrum and discuss some of the prospects for a new (multi-particle) astronomy. Finally, we outline how extraterrestrial neutrino fluxes can be used to probe new physics beyond the electroweak scale.Comment: Higher resolution version of Fig. 7 is available at http://www.angelfire.com/id/dtorres/down3.html. Solicited review article prepared for Reports on Progress in Physics, final versio