Hydroxylation of benzphetamine and other drugs by a solubilized form of cytochrome P-450 from liver microsomes: Lipid requirement for drug demethylation

A solubilized hepatic microsomal enzyme system previously shown to catalyze the [omega]-hydroxylation of fatty acids also catalyzes the hydroxylation of drugs. Benzphetamine, aminopyrine, ethylmorphine, hexobarbital, norcodeine, and -nitroanisole undergo aerobic demethylation in the presence of NADPH and the resolved enzyme system. The required submicrosomal components for benzphetamine demethylation, as determined either by formaldehyde liberation or by NADPH oxidation, are cytochrome P-450, NADPH-cytochrome P-450 reductase, and a heat-stable lipid fraction. Similar requirements were shown for the oxidation of aminopyrine, ethylmorphine, and hexobarbital. Laurate and benzphetamine were found to be mutually inhibitory, as would be expected if a common "methyl hydroxylase" were involved. The solubilized cytochrome P-450 preparation exhibits a difference spectrum in the presence of benzphetamine with a peak at 392 m[mu] and a trough at 427 m[mu] and difference spectra with aniline and hexobarbital typical of those obtained with the microsomal bound form of this hemoprotein.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32916/1/0000296.pd

The CBM-opathies—A Rapidly Expanding Spectrum of Human Inborn Errors of Immunity Caused by Mutations in the CARD11-BCL10-MALT1 Complex

The caspase recruitment domain family member 11 (CARD11 or CARMA1)—B cell CLL/lymphoma 10 (BCL10)—MALT1 paracaspase (MALT1) [CBM] signalosome complex serves as a molecular bridge between cell surface antigen receptor signaling and the activation of the NF-κB, JNK, and mTORC1 signaling axes. This positions the CBM complex as a critical regulator of lymphocyte activation, proliferation, survival, and metabolism. Inborn errors in each of the CBM components have now been linked to a diverse group of human primary immunodeficiency diseases termed “CBM-opathies.” Clinical manifestations range from severe combined immunodeficiency to selective B cell lymphocytosis, atopic disease, and specific humoral defects. This surprisingly broad spectrum of phenotypes underscores the importance of “tuning” CBM signaling to preserve immune homeostasis. Here, we review the distinct clinical and immunological phenotypes associated with human CBM complex mutations and introduce new avenues for targeted therapeutic intervention

Hidden Symmetries and Dirac Fermions

In this paper, two things are done. First, we analyze the compatibility of Dirac fermions with the hidden duality symmetries which appear in the toroidal compactification of gravitational theories down to three spacetime dimensions. We show that the Pauli couplings to the p-forms can be adjusted, for all simple (split) groups, so that the fermions transform in a representation of the maximal compact subgroup of the duality group G in three dimensions. Second, we investigate how the Dirac fermions fit in the conjectured hidden overextended symmetry G++. We show compatibility with this symmetry up to the same level as in the pure bosonic case. We also investigate the BKL behaviour of the Einstein-Dirac-p-form systems and provide a group theoretical interpretation of the Belinskii-Khalatnikov result that the Dirac field removes chaos.Comment: 30 page

Chemomechanics of ionically conductive ceramics for electrical energy conversion and storage

Functional materials for energy conversion and storage exhibit strong coupling between electrochemistry and mechanics. For example, ceramics developed as electrodes for both solid oxide fuel cells and batteries exhibit cyclic volumetric expansion upon reversible ion transport. Such chemomechanical coupling is typically far from thermodynamic equilibrium, and thus is challenging to quantify experimentally and computationally. In situ measurements and atomistic simulations are under rapid development to explore how this coupling can be used to potentially improve both device performance and durability. Here, we review the commonalities of coupling between electrochemical and mechanical states in fuel cell and battery materials, illustrating with specific cases the progress in materials processing, in situ characterization, and computational modeling and simulation. We also highlight outstanding questions and opportunities in these applications – both to better understand the limiting mechanisms within the materials and to significantly advance the durability and predictability of device performance required for renewable energy conversion and storage.United States. Dept. of Energy (Basic Energy Sciences Division of Materials Sciences and Engineering, grant DE-SC0002633)United States. Dept. of Energy (Office of Science, Graduate Fellowship Program (DOE SCGF))United States. American Recovery and Reinvestment Act of 2009 (ORISE-ORAU, contract no. DE-AC05-06OR23100))United States. Dept. of Energy. Division of Materials Sciences and Engineering (MIT/DMSE Salapatas Fellowship)United States. Air Force Office of Scientific Research (Presidential Early Career Award in Science and Engineering (PECASE)

Computational neuroscience: a frontier of the 21st century

The human brain is a biological organ, weighing about three pounds or 1.4 kg, that determines our behaviors, thoughts, emotions and consciousness. Although comprising only 2% of the total body weight, the brain consumes about 20% of the oxygen entering the body. With the expensive energy demand, the brain enables us to perceive and act upon the external world, as well as reflect on our internal thoughts and feelings. The brain is actually never at ‘rest’. Brain activities continue around the clock, ranging from functions enabling human–environment interactions to housekeeping during sleep, including processes such as synaptic homeostasis and memory formation. Whereas one could argue that sciences in the last century were dominated by physics and molecular biology, in the current century one of our major challenges is to elucidate how the brain works. A full understanding of brain functions and malfunctions is likely the most demanding task we will ever have

Genetic risk prediction of atrial fibrillation

Background—Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods—To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1x10-3 to <1x10-8 in a prior independent genetic association study. Results—Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13-1.46; P=1.5x10-4) to 1.67 (25 variants; 95%CI, 1.47-1.90; P=9.3x10-15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95%CI, 1.39-4.58; P=2.7x10-3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20-4.40; P=0.01). Conclusions—Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms

The funding and use of high-cost medicines in Australia: the example of anti-rheumatic biological medicines

BACKGROUND: Subsidised access to high-cost medicines in Australia is restricted under national programs (the Pharmaceutical Benefits Scheme, PBS, and the Repatriation Pharmaceutical Benefits Scheme, RPBS) with a view to achieving cost-effective use. The aim of this study was to examine the use and associated government cost of biological agents for treating rheumatoid arthritis over the first two years of subsidy, and to compare these data to the predicted outcomes. METHODS: National prescription and expenditure data for the biologicals, etanercept, infliximab, adalimumab, and anakinra were collected and analysed for the period August 2003 to July 2005. Dispensing data on biologicals sorted by the metropolitan, rural and remote zones and by prescriber major specialty were also examined. RESULTS: A total of 27,970 prescriptions for biologicals was reimbursed. The government expenditure was A$53.1 million, representing only 19$52 million) and the remainder by the RPBS. Approximately 62% of the prescriptions were for concessional patients (A$32.9 million). There was considerable variability in the use of biologicals across Australian states and territories, usage roughly correlating with the per capita adjusted number of rheumatologists. The total number of prescriptions continued to increase over the study period. Etanercept was the most highly prescribed agent (74% by number of prescriptions), although its use was beginning to plateau. Use of adalimumab increased steadily. Use of infliximab and anakinra was considerably lower. The resultant health outcomes for individual patients are unknown. Prescribers from capital cities and other metropolitan centres provided a majority of prescriptions of biologicals (89%). CONCLUSION: The overall uptake of biologicals for treating rheumatoid arthritis over the first two years of PBS subsidy was considerably lower than expected. Long-term safety concerns and the expanded clinical uses of these drugs emphasise the need for evaluation. It is essential that there is comprehensive, ongoing analysis of utilisation data, associated expenditure and, importantly, patient outcomes in order to enhance accountability, efficiency and equity of policies that allocate substantial resources to subsidising national access to high-cost medicines

The Inferred Evolution of the Cold Gas Properties of CANDELS Galaxies at 0.5 \u3c \u3cem\u3ez\u3c/em\u3e \u3c 3.0

We derive the total cold gas, atomic hydrogen, and molecular gas masses of approximately 24 000 galaxies covering four decades in stellar mass at redshifts 0.5 \u3c z \u3c 3.0, taken from the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey survey. Our inferences are based on the inversion of a molecular hydrogen based star formation law, coupled with a prescription to separate atomic and molecular gas. We find that: (1) there is an increasing trend between the inferred cold gas (H i and H2), H i, and H2 mass and the stellar mass of galaxies down to stellar masses of 108 M⊙ already in place at z = 3; (2) the molecular fractions of cold gas increase with increasing stellar mass and look-back time; (3) there is hardly any evolution in the mean H i content of galaxies at fixed stellar mass; (4) the cold gas fraction and relative amount of molecular hydrogen in galaxies decrease at a relatively constant rate with time, independent of stellar mass; (5) there is a large population of low stellar mass galaxies dominated by atomic gas. These galaxies are very gas rich, but only a minor fraction of their gas is molecular; 6) the ratio between star formation rate (SFR) and inferred total cold gas mass (Hi + H2) of galaxies (i.e. star formation efficiency; SFE) increases with star formation at fixed stellar masses. Due to its simplicity, the presented approach is valuable to assess the impact of selection biases on small samples of directly observed gas masses and to extend scaling relations down to stellar mass ranges and redshifts that are currently difficult to probe with direct measurements of gas content

Measurement of the muon anti-neutrino double-differential cross section for quasi-elastic scattering on hydrocarbon at~Eν∼3.5E_\nu \sim 3.5 GeV

We present double-differential measurements of anti-neutrino quasi-elastic scattering in the MINERvA detector. This study improves on a previous single differential measurement by using updated reconstruction algorithms and interaction models, and provides a complete description of observed muon kinematics in the form of a double-differential cross section with respect to muon transverse and longitudinal momentum. We include in our signal definition zero-meson final states arising from multi-nucleon interactions and from resonant pion production followed by pion absorption in the primary nucleus. We find that model agreement is considerably improved by a model tuned to MINERvA inclusive neutrino scattering data that incorporates nuclear effects such as weak nuclear screening and two-particle, two-hole enhancements.Comment: 47 pages, 31 figure