Arsenic-Based Antineoplastic Drugs and Their Mechanisms of Action

Arsenic-based compounds have become accepted agents for cancer therapy providing high rates of remission of some cancers such as acute promyelocytic leukemia (APL). The mechanisms by which arsenic-containing compounds kill cells and reasons for selective killing of only certain types of cancer cells such as APLs have recently been delineated. This knowledge was gained in parallel with increasing understanding and awareness of the importance of intracellular redox systems and regulation of the production of reactive oxygen species (ROS) by controlling mitochondrial function. Many of the targets for the arsenic-containing compounds are mitochondrial proteins involved in regulating the production of ROS. Inhibition of these proteins by disulfide linkage of vicinal thiol groups often leads to increased production of ROS and induction of apoptotic signalling pathways. Sensitivity or resistance to the actions of arsenic-containing compounds on cancer cells and normal cells depends on the levels of transport systems for their uptake or efflux from the cells as well as their redox defence mechanisms. The exact mechanisms of arsenic toxicity as well as its anticancer properties are likely to be related and these aspects of arsenic metabolism are covered in this review. Greater understanding of the mechanisms of action of arsenic will help determine the risks of human exposure to this chemical. Novel organic arsenic-containing compounds and the lessons learned from studying their selective sensitivity in targeting dividing endothelial cells to inhibit angiogenesis raise the future possibility for designing better targeted antineoplastic arsenic-containing compounds with less toxicity to normal cells

Scientific Objectives, Measurement Needs, and Challenges Motivating the PARAGON Aerosol Initiative

Aerosols are involved in a complex set of processes that operate across many spatial and temporal scales. Understanding these processes, and ensuring their accurate representation in models of transport, radiation transfer, and climate, requires knowledge of aerosol physical, chemical, and optical properties and the distributions of these properties in space and time. To derive aerosol climate forcing, aerosol optical and microphysical properties and their spatial and temporal distributions, and aerosol interactions with clouds, need to be understood. Such data are also required in conjunction with size-resolved chemical composition in order to evaluate chemical transport models and to distinguish natural and anthropogenic forcing. Other basic parameters needed for modeling the radiative influences of aerosols are surface reflectivity and three-dimensional cloud fields. This large suite of parameters mandates an integrated observing and modeling system of commensurate scope. The Progressive Aerosol Retrieval and Assimilation Global Observing Network (PARAGON) concept, designed to meet this requirement, is motivated by the need to understand climate system sensitivity to changes in atmospheric constituents, to reduce climate model uncertainties, and to analyze diverse collections of data pertaining to aerosols. This paper highlights several challenges resulting from the complexity of the problem. Approaches for dealing with them are offered in the set of companion papers

Mechanical design engineering. NASA/university advanced design program: Lunar Bulk Material Transport Vehicle

The design of a Lunar Bulk Material Transport Vehicle (LBMTV) is discussed. Goals set in the project include a payload of 50 cubic feet of lunar soil with a lunar of approximately 800 moon-pounds, a speed of 15 mph, and the ability to handle a grade of 20 percent. Thermal control, an articulated steering mechanism, a dump mechanism, a self-righting mechanism, viable power sources, and a probable control panel are analyzed. The thermal control system involves the use of small strip heaters to heat the housing of electronic equipment in the absence of sufficient solar radiation and multi-layer insulation during periods of intense solar radiation. The entire system uses only 10 W and weighs about 60 pounds, or 10 moon-pounds. The steering mechanism is an articulated steering joint at the center of the vehicle. It utilizes two actuators and yields a turning radius of 10.3 feet. The dump mechanism rotates the bulk material container through an angle of 100 degree using one actuator. The self-righting mechanism consists of two four bar linkages, each of which is powered by the same size actuator as the other linkages. The LBMTV is powered by rechargeable batteries. A running time of at least two hours is attained under a worst case analysis. The weight of the batteries is 100 pounds. A control panel consisting of feedback and control instruments is described. The panel includes all critical information necessary to control the vehicle remotely. The LBMTV is capable of handling many types of cargo. It is able to interface with many types of removable bulk material containers. These containers are made to interface with the three-legged walker, SKITTER. The overall vehicle is about 15 feet in length and has a weight of about 1000 pounds, or 170 lunar pounds

Reply to ''Comments on 'Why Hasn't Earth Warmed as much as Expected?'''

In response to our article, Why Hasnt Earth Warmed as Much as Expected? (2010), Knutti and Plattner (2012) wrote a rebuttal. The term climate sensitivity is usually defined as the change in global mean surface temperature that is produced by a specified change in forcing, such as a change in solar heating or greenhouse gas concentrations. We had argued in the 2010 paper that although climate models can reproduce the global mean surface temperature history over the past century, the uncertainties in these models, due primarily to the uncertainty in climate forcing by airborne particles, mean that the models lack the confidence to actually constrain the climate sensitivity within useful limits for climate prediction. Knutti and Plattner are climate modelers, and they argued essentially that because the models could reproduce the surface temperature history, the issue we raised was moot. Our response amounts to straightening out this confusion; for the models to be constraining, they must be able to reproduce the surface temperature history with sufficient confidence, not just to match the measurements, but to exclude alternative histories. As before, we concluded that if we can actually make the aerosol measurements using currently available, state-of-the-art techniques, we can determine the aerosol climate forcing to the degree required to constrain that aspect of model climate sensitivity. A technical issue relating to the timescale over which a change in CO2 emissions would be equilibrated in the environmental energy balance was also discussed, again, a matter of differences in terminology

The Changing Role of Ancillary Health Care Service Providers: An Evaluation of Health Diagnostic Laboratory, Inc.

In an effort to reduce cost and improve quality, health care payers have enacted a number of incentives to motivate providers to focus their efforts on achieving better clinical outcomes and reducing the prevalence and progression of disease. In response to these incentives, providers are entering into new arrangements such as accountable care organizations and patient-centered medical homes to redesign delivery processes and achieve quality and cost objectives. This article reports the results of a study designed to evaluate the impact on cost and quality of care resulting from services provided by Health Diagnostic Laboratory, Inc., a clinical laboratory with a comprehensive care model. The results show that patients who utilized these laboratory services experienced lower total cost of care (23% reduction, P \u3c 0.01) and improved lipid profiles during the follow-up period. Total cost reductions were related to cost reductions found in both inpatient and ambulatory care. These findings suggest that accountable care organizations, patient-centered medical homes, and other groups entering shared savings initiatives should consider the potential role ancillary service providers with comprehensive care models can play in the delivery of integrated care. (Population Health Management 2014; 17: 121-126

Demodulation and de-multiplexing of a fibre Bragg grating sensor array using volume holograms

The demodulation of a Wavelength Division Multiplexed FBG sensor array by a matching array of holograms hosted within a Volume Holographic (VH) material is considered within this thesis. The FBG sensor elements possess separate quiescent wavelengths and operate within different wavelength ranges. The edge of the transfer function of the demodulating holographic element is aligned with the operating range of the matching sensor element. The holographic element then diffracts a fraction of the sensor signal depending on its instantaneous wavelength. The signals from each of the sensor elements are also diffracted through separate angles to matching detectors so de-multiplexing the sensor array. A scheme using narrow bandwidth holographic transfer functions to demodulate a two element strain sensor array fabricated 4nm apart is reported. The transfer functions and the hysteresis within the PZT actuator, applying the strain, are represented mathematically and used to process results. These are compared with a normalised saw-tooth voltage waveform applied to the PZT to achieve a high Pearson correlation factor of 0.9992. The holograms however possessed poor diffraction efficiency <1% so severely degrading strain resolution. The crosstalk between the sensors’ channels is measured as -8.3dB. The demodulation scheme is intensity based so is susceptible to fluctuations in source intensity and fibre bend losses. An intensity reference scheme is therefore demonstrated using two holograms to demodulate a single FBG strain sensor. The sensor’s signal is divided by the two holograms and the intensity of the respective parts recorded on matched photo-detectors. Ratiometric detection is then used to identify changes in applied strain while disregarding fluctuations in source intensity and fibre bend losses. The standard difference over sum equation for ratiometric detection however is modified to take account of the respective holographic transfer functions.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The role of transposable element clusters in genome evolution and loss of synteny in the rice blast fungus Magnaporthe oryzae

BACKGROUND: Transposable elements are abundant in the genomes of many filamentous fungi, and have been implicated as major contributors to genome rearrangements and as sources of genetic variation. Analyses of fungal genomes have also revealed that transposable elements are largely confined to distinct clusters within the genome. Their impact on fungal genome evolution is not well understood. Using the recently available genome sequence of the plant pathogenic fungus Magnaporthe oryzae, combined with additional bacterial artificial chromosome clone sequences, we performed a detailed analysis of the distribution of transposable elements, syntenic blocks, and other features of chromosome 7. RESULTS: We found significant levels of conserved synteny between chromosome 7 and the genomes of other filamentous fungi, despite more than 200 million years of divergent evolution. Transposable elements are largely restricted to three clusters located in chromosomal segments that lack conserved synteny. In contradiction to popular evolutionary models and observations from other model organism genomes, we found a positive correlation between recombination rate and the distribution of transposable element clusters on chromosome 7. In addition, the transposable element clusters are marked by more frequent gene duplications, and genes within the clusters have greater sequence diversity to orthologous genes from other fungi. CONCLUSION: Together, these data suggest that transposable elements have a profound impact on the M. oryzae genome by creating localized segments with increased rates of chromosomal rearrangements, gene duplications and gene evolution

Exceptional uranium(VI)-nitride triple bond covalency from ¹⁵N nuclear magnetic resonance spectroscopy and quantum chemical analysis.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-09-01, epub 2021-09-24Publication status: PublishedFunder: RCUK | Engineering and Physical Sciences Research Council (EPSRC); Grant(s): EP/M027015/1, EP/K024000/1, EP/S033181/1Funder: European Research Council; Grant(s): 612724Determining the nature and extent of covalency of early actinide chemical bonding is a fundamentally important challenge. Recently, X-ray absorption, electron paramagnetic, and nuclear magnetic resonance spectroscopic studies have probed actinide-ligand covalency, largely confirming the paradigm of early actinide bonding varying from ionic to polarised-covalent, with this range sitting on the continuum between ionic lanthanide and more covalent d transition metal analogues. Here, we report measurement of the covalency of a terminal uranium(VI)-nitride by 15N nuclear magnetic resonance spectroscopy, and find an exceptional nitride chemical shift and chemical shift anisotropy. This redefines the 15N nuclear magnetic resonance spectroscopy parameter space, and experimentally confirms a prior computational prediction that the uranium(VI)-nitride triple bond is not only highly covalent, but, more so than d transition metal analogues. These results enable construction of general, predictive metal-ligand 15N chemical shift-bond order correlations, and reframe our understanding of actinide chemical bonding to guide future studies

Identification of Small Molecules that Enhance Synaptogenesis Using Synapse Microarrays

Synaptic function is affected in many brain diseases and disorders. Technologies for large-scale synapse assays can facilitate identification of drug leads. Here we report a “synapse microarray” technology that enables ultra-sensitive, high-throughput, and quantitative screening of synaptogenesis. Our platform enables the induction of synaptic structures in regular arrays by precise positioning of non-neuronal cells expressing synaptic proteins, while allowing neurites to grow freely around these cells. The technology increases by tenfold the sensitivity of the traditional assays, and simultaneously decreases the time required to capture synaptogenic events by an order of magnitude. It is readily incorporated into multiwell formats compatible with industrial high-throughput screening platforms. Using this technology, we screened a chemical library and identified novel histone deacetylase inhibitors that improve neuroligin-1 induced synaptogenesis via modulating class-I histone deacetylases. We also found a structure-activity relationship for designing novel potent histone deacetylase inhibitors, which can be applied towards development of new therapeutics