The effects of maribavir on the autophosphorylation of ganciclovir resistant mutants of the cytomegalovirus UL97 protein

BACKGROUND: The UL97 protein kinase of human cytomegalovirus phosphorylates the antiviral drug ganciclovir and is the target of maribavir action. A detailed enzyme kinetic analysis of maribavir on the various enzymatic functions of wild type and ganciclovir resistant forms of UL97 is required. METHODS: Wild type and site directed mutant forms of the human cytomegalovirus UL97 gene product were expressed using recombinant baculoviruses and the purified products used to assess the effects of maribavir on the ganciclovir (GCV) kinase and protein kinase (PK) activities. RESULTS: Maribavir was a potent inhibitor of the autophosporylation of the wild type and all the major GCV resistant UL97 mutants analysed (M460I, H520Q, A594V and L595F) with a mean IC50 of 35 nM. The M460I mutation resulted in hypersensitivity to maribavir with an IC50 of 4.8 nM. A maribavir resistant mutant of UL97 (L397R) was functionally compromised as both a GCV kinase and a protein kinase (~ 10% of wild type levels). Enzyme kinetic experiments demonstrated that maribavir was a competitive inhibitor of ATP with a Ki of 10 nM. DISCUSSION: Maribavir is a potent competitive inhibitor of the UL97 protein kinase function and shows increased activity against the M460I GCV-resistant mutant which may impact on the management of GCV drug resistance in patients

G Protein Coupled Receptors in Embryonic Stem Cells: A Role for Gs-Alpha Signaling

Background: Identification of receptor mediated signaling pathways in embryonic stem (ES) cells is needed to facilitate strategies for cell replacement using ES cells. One large receptor family, largely uninvestigated in ES cells, is G protein coupled receptors (GPCRs). An important role for these receptors in embryonic development has been described, but little is known about GPCR expression in ES cells. Methodology/Principal Findings: We have examined the expression profile of 343 different GPCRs in mouse ES cells demonstrating for the first time that a large number of GPCRs are expressed in undifferentiated and differentiating ES cells, and in many cases at high levels. To begin to define a role for GPCR signaling in ES cells, the impact of activating Gs-alpha, one of the major alpha subunits that couples to GPCRs, was investigated. Gs-alpha activation resulted in larger embryoid bodies (EBs), due, in part, to increased cell proliferation and prevented the time-related decline in expression of transcription factors important for maintaining ES cell pluripotency. Significance/Conclusions: These studies suggest that Gs-alpha signaling contributes to ES cell proliferation and pluripotency and provide a framework for further investigation of GPCRs in ES cells

Analysis of pin fins with radiation

The design of fins for heat transfer enhancement remains a topic of great interest in a number of engineering areas and applications, despite a broad and deep prior literature on the subject. Rapid prediction of the effects of convection, conduction and radiation is still an area of concern. For hot-flow conditions, the fin is normally mounted in a cooled surface, leading to substantial axial conduction. Also, radiation plays a very important role in hot flow conditions. One can apply detailed computational methods for simultaneous convection, conduction and radiation heat transfer, but such approaches are not suitable for rapid, routine design studies. So, there is still a place for approximate analytic methods, and that is the subject of this paper. We have extended the traditional pin fin analysis to include a more realistic radiation treatment and also considered variable thermal conductivity, variable heat transfer coefficients over the tip and sides of the fin with variable area distribution, variable internal heat generation and then produced a MATLAB solution procedure for routine use by designers and analysts.Papers presented at the 13th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Portoroz, Slovenia on 17-19 July 2017 .International centre for heat and mass transfer.American society of thermal and fluids engineers

Natural and anthropogenic lead in sediments of the Rotorua lakes, New Zealand

Global atmospheric sources of lead have increased more than 100-fold over the past century as a result of deforestation, coal combustion, ore smelting and leaded petroleum. Lead compounds generally accumulate in depositional areas across the globe where, due to low solubility and relative freedom from microbial degradation, the history of their inputs is preserved. In lakes there is rapid deposition and often little bioturbation of lead, resulting in an excellent depositional history of changes in both natural and anthropogenic sources. The objective of this study was to use sediments from a regionally bounded set of lakes to provide an indication of the rates of environmental inputs of lead whilst taking into account differences of trophic state and lead exposure between lakes. Intact sediment gravity cores were collected from 13 Rotorua lakes in North Island of New Zealand between March 2006 and January 2007. Cores penetrated sediments to a depth of 16–30 cm and contained volcanic tephra from the 1886 AD Tarawera eruption. The upper depth of the Tarawera tephra enabled prescription of a date for the associated depth in the core (120 years). Each core showed a sub-surface peak in lead concentration above the Tarawera tephra which was contemporaneous with the peak use of lead alkyl as a petroleum additive in New Zealand. An 8 m piston core was taken in the largest of the lakes, Lake Rotorua, in March 2007. The lake is antipodal to the pre-industrial sources of atmospheric lead but still shows increasing lead concentrations from <2 up to 3.5 μg g−1 between the Whakatane eruption (5530 ± 60 cal. yr BP) and the Tarawera eruption. Peaks in lead concentration in Lake Rotorua are associated with volcanic tephras, but are small compared with those arising from recent anthropogenic-derived lead deposition. Our results show that diagenetic processes associated with iron, manganese and sulfate oxidation-reduction, and sulfide precipitation, act to smooth distributions of lead from anthropogenic sources in the lake sediments. The extent of this smoothing can be related to changes in sulfate availability and reduction in sulfide driven by differences in trophic status amongst the lakes. Greatest lead mobilisation occurs in mesotrophic lakes during seasonal anoxia as iron and manganese are released to the porewater, allowing upward migration of lead towards the sediment–water interface. This lead mobilisation can only occur if sulfides are not present. The sub-surface peak in lead concentrations in lake sediments ascribed to lead alkyl in petroleum persists despite the diagenetic processes acting to disperse lead within the sediments and into the overlying water

Expression of executive control in situational context: Effects of facilitating versus restraining cues on snack food consumption

Objectives: To examine the effects of executive function (EF) on objectively measured high-calorie snack food consumption in 2 age groups and to explore the moderating influence of environmental cues. Methods: In Study 1, 43 older adults (Mage = 74.81) and in Study 2, 79 younger adults (Mage = 18.71) completed measures of EF and subsequently participated in a bogus taste-test paradigm wherein they were required to rate 3 highly appetitive (but high-calorie) snack foods on taste and texture. Grams of snack food consumed was measured covertly in the presence randomly assigned contextual cues (explicit semantic cues in Study 1; implicit visual cues in Study 2) that were facilitating or restraining in nature. Results: Findings indicated that in both age groups, stronger EF predicted lower consumption of snack foods across conditions, and the effects of EF were most pronounced in the presence of facilitating cues. Conclusions: Older and younger adults with weaker EF tend to consume more high-calorie snack food compared with their stronger EF counterparts. These tendencies appear to be especially amplified in the presence of facilitating cues

DeepBrain: Functional Representation of Neural In-Situ Hybridization Images for Gene Ontology Classification Using Deep Convolutional Autoencoders

This paper presents a novel deep learning-based method for learning a functional representation of mammalian neural images. The method uses a deep convolutional denoising autoencoder (CDAE) for generating an invariant, compact representation of in situ hybridization (ISH) images. While most existing methods for bio-imaging analysis were not developed to handle images with highly complex anatomical structures, the results presented in this paper show that functional representation extracted by CDAE can help learn features of functional gene ontology categories for their classification in a highly accurate manner. Using this CDAE representation, our method outperforms the previous state-of-the-art classification rate, by improving the average AUC from 0.92 to 0.98, i.e., achieving 75% reduction in error. The method operates on input images that were downsampled significantly with respect to the original ones to make it computationally feasible

What is a sentinel node? Re-evaluating the 10% rule for sentinel lymph node biopsy in melanoma

Introduction Many surgeons use the “10% rule” to define whether a lymph node is a sentinel node (SLN) when staging malignant melanoma. However, this increases the number of SLN removed and the time and cost of the procedure. We examined the impact of raising this threshold on the accuracy of the procedure. Methods We reviewed the records of 561 patients with melanoma (624 basins) who underwent SLN with technetium Tc99 labeled sulfur colloid using a definition of a SLN as 10% of that of the node with the highest counts per minute (CPM). Results Of the 624 basins, 154 (25%) were positive for metastases. An average of 1.9 nodes per basin were removed (range 1–6). Metastases were found in the hottest node in 137 cases (89% of positive basins, 97% of basins overall). Increasing the threshold above 10% decreased the number of nodes excised and the costs involved, but incrementally raised the number of false negative cases above baseline (a 4% increase for a “20% rule,” 5% for a “30% rule,” 6% for a “40% rule,” and 7% for a “50% rule”). Taking only the hottest node would raise the false negative rate by 11%. Conclusions Although using thresholds higher than 10% for the definition of a SLN will minimize the extent of surgery and decrease the costs associated with the procedure, it will compromise the accuracy of the procedure and is not recommended. J. Surg. Oncol. 2007;95:623–628. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56055/1/20729_ftp.pd

Electronic properties of solution-processed Cu(In,Ga)(S,Se)2 solar cells using metal chalcogenides and amine-thiol solvent mixtures

This work examines the effects of post-deposition air-annealing on the electronic properties of solution-processed heterojunction CIGS solar cells. The annealing in air of the CIGS/CdS interface was found to have positive effects on the device performance with an increase in all PV parameters even after annealing times as short as 5 min. A VOC increase of <; 130 mV was caused by the reduced surface and grain boundary recombination through passivation of surface Se deficiencies with oxygen atoms. Prolonged annealing causes charge redistribution and diffusion of mobile elements such as Cu and Cd deeper into the absorber bulk however, resulting in lower carrier density and deeper defects with increased annealing time. These were observed through capacitance-voltage profiling and admittance spectroscopy

Water based spray pyrolysis of metal-oxide solutions for Cu2ZnSn(S,Se)4 solar cells using low toxicity amine/thiol complexants

Cu ZnSnS(e) 2 4 deposited using solution processes has potential for terrawatt-scale deployment. The champion highest efficiency Cu ZnSn(S,Se) 2 4 cell published in literature is spin-coated using the highly dangerous hydrazine which is an impractically scalable solvent and deposition combination. As an alternative solvent amine-thiol mixtures have shown to complex with a wide range of binary chalcogenides with much lower health risks than hydrazine. Herein we present two further toxicity reductions, first by employing a less harmful amine-thiol pairing and second by using water as a diluting solvent. We exclude extraneous elements from the precursor solution such as halogens and with a sub-micron thickness crystalline absorber achieve an efficiency of 6.8 %. With the modified solution deposited by ultrasonic spray pyrolysis, this solution process is scalable, abundant, and relatively non-toxic