Characterization of Apo-Form Selective Inhibition of Indoleamine 2,3-Dioxygenase**

Indoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As it is an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of IDO1 inhibitors with various mechanisms of inhibition is of great interest. Comparison of an apo-form-binding IDO1 inhibitor (GSK5628) to the heme-coordinating compound, epacadostat (Incyte), allows us to explore the details of the apo-binding inhibition of IDO1. Herein, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1), whereas epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, previously undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition might help design superior inhibitors or could confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.     

Field response ofDendroctonus brevicomis toexo-brevicomin,frontalin, and myrcene released at two proportions and three levels

Racemicezo-brevicomin, racemic frontalin, and myrcene were released at two proportions (51400 and 111), each at three levels (1 ×, 10 ×, and 100 ×) in a ponderosa pine forest in central California. The 51400 mix was based on an estimate of the relative amounts released from a ponderosa pine under attack by the western pine beetle,Dendroctonus brevicomis. MoreD. brevicomis were trapped at a source of the three compounds released at 51400 than were trapped at a source released at 111, at all three levels, but this difference was statistically significant only at the 1 × and 10 × levels. Sex ratio of trapped beetles and distribution of catch at the source of attractant and 5 m away apparently did not differ between relative release rates.Coleoptera: Scolytidae.Trade names are mentioned solely for information. No endorsement by the U.S. Department of Agriculture is implied.     

Behavior of the western pine beetle during host colonization

After living ponderosa pines were baited with either female-infested bolts or synthetic pheromones,Dendroctonus brevicomis were caught on sticky screens throughout trapping periods of 15–46 days; however, large numbers of beetles were trapped during only a small portion (5–10 days) of these trapping periods. The most attractive portions of trees attacked contained 3–6 beetles dm², in galleries ca. 2 cm long. Catch increased following addition of males to female-infested bolts, supporting the hypothesis that male-produced frontalin is an attractive pheromone of the western pine beetle. Catch at bolts removed from trees under attack was strongly dependent upon levels of boring activity. We found no evidence of interruption of the response to attractants during host colonization.Coleoptera: Scolytidae. Trade names and commercial enterprises or products are mentioned solely for information and do not constitute endorsement by the U.S. Department of Agriculture or University of California.     

Effects of food deprivation on hunger motivation in golden hamsters (Mesocricetus auratus).

Unlike most other laboratory animals, golden hamsters do not typically increase their food intake following periods of food shortage. It is possible that the hamster feeding system may not be programmed to respond to the metabolic consequences of deprivation; expressed in motivational terms, deprived hamsters would not be hungrier than usual and therefore would not eat more than usual. However, because food consumption is influenced both by hunger motivation and by the motivation to stop eating, the amount of food eaten is not necessarily the best measure of hunger motivation. Four experiments were conducted, revealing that acute food deprivation has significant effects on latency to eat, speed of eating, consumption of a quinine-adulterated diet, open-field activity, and persistence of performance of an instrumental response during extinction. These results constitute convergent evidence that food deprivation increases the hunger motivation of golden hamsters, although deprivation does not lead to increases in the total food intake. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Antenatal phenobarbital therapy and neonatal outcome. II: Neurodevelopmental outcome at 36 months

X-linked liver glycogenosis type II (XLG II) is a recently described X-linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.     

A double-recessed Al0.24GaAs/In0.16GaAspseudomorphic HEMT for Ka- and 𝒬-band power applications

A double-recessed 0.2-μm-gate-length pseudomorphic HEMT (PHEMT) has been demonstrated with 500 mW of output power (833 mW/mm of gate periphery), 6-dB gain, and 35% power-added efficiency (PAE) at 32 GHz. At 44 GHz, the device exhibited 494 mW of output power (823 mW/mm), 4.3-dB gain, and 30% PAE. This level of performance is attributed to excellent MBE material, optimized epitaxial layer design, and the use of individual source vias and of double recess with tight channel dimensions. Excellent 3-in-wafer uniformity was also observed: DC yield was greater than 95% and the interquartile range for all DC parameters was less than 20% of the median value (most are significantly lower)     

Non-homogeneous extracellular resistivity affects the current-source density profiles of up-down state oscillations

Rhythmic local field potential (LFP) oscillations observed during deep sleep are the result of synchronized electrical activities of large neuronal ensembles, which consist of alternating periods of activity and silence, termed 'up' and 'down' states, respectively. Current-source density (CSD) analysis indicates that the up states of these slow oscillations are associated with current sources in superficial cortical layers and sinks in deep layers, while the down states display the opposite pattern of source-sink distribution. We show here that a network model of up and down states displays this CSD profile only if a frequency-filtering extracellular medium is assumed. When frequency filtering was modelled as inhomogeneous conductivity, this simple model had considerably more power in slow frequencies, resulting in significant differences in LFP and CSD profiles compared with the constant-resistivity model. These results suggest that the frequency-filtering properties of extracellular media may have important consequences for the interpretation of the results of CSD analysis.