1,787 research outputs found
Identifying Novel Leads Using Combinatorial Libraries: Issues and Successes
Chemically generated libraries of small, non-oligomeric compounds are being widely embraced by researchers in both industry and academia. There has been a steady development of new chemistries and equipment applied to library generation so it is now possible to synthesize almost any
desired class of compound. However, there are still important issues to consider that range from what specific types of compounds should be made to concerns such as sample resynthesis, structural confirmation of the hit identified, and how to best integrate this technology into a pharmaceutical
drug discovery operation. This paper illustrates our approach to new lead discovery (individual, diverse, drug-like molecules of known structural identity using a simple, spatially addressable parallel synthesis approach to prepare Multiple Diverse as well as Universal Libraries) and describes
some representative examples of chemistries we had developed within these approaches (preparation of bis-benzamide phenols, thiophenes, pyrrolidines, and highly substituted biphenyls). Finally, the manuscript concludes by addressing some the present concerns that still must be considered in
this field
Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.
The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment
Energy Efficient Engine Low Pressure Subsystem Aerodynamic Analysis
The objective of this study was to demonstrate the capability to analyze the aerodynamic performance of the complete low pressure subsystem (LPS) of the Energy Efficient Engine (EEE). Detailed analyses were performed using three- dimensional Navier-Stokes numerical models employing advanced clustered processor computing platforms. The analysis evaluates the impact of steady aerodynamic interaction effects between the components of the LPS at design and off- design operating conditions. Mechanical coupling is provided by adjusting the rotational speed of common shaft-mounted components until a power balance is achieved. The Navier-Stokes modeling of the complete low pressure subsystem provides critical knowledge of component acro/mechanical interactions that previously were unknown to the designer until after hardware testing
Investigating the feasibility of using asphalt pavements as a source of heating
This paper evaluates the feasibility of using asphalt pavements as solar energy collectors with copper pipes embedded below the surfaces. Quartzite was investigated as a replacement for limestone aggregate in asphalt for thermal enhancement. Samples of both asphalt types were tested for indirect stiffness modulus, indirect fatigue, permanent deformation and thermal conductivity. The pipe networks system was also tested. The results indicate that limestone has a better performance in load bearing capacity except fatigue life but the thermal conductivity of the quartzite mixture is higher. With a greater thermal conductivity in the upper layer, the thermal efficiency of the network can be significantly improved
Valence bond solid formalism for d-level one-way quantum computation
The d-level or qudit one-way quantum computer (d1WQC) is described using the
valence bond solid formalism and the generalised Pauli group. This formalism
provides a transparent means of deriving measurement patterns for the
implementation of quantum gates in the computational model. We introduce a new
universal set of qudit gates and use it to give a constructive proof of the
universality of d1WQC. We characterise the set of gates that can be performed
in one parallel time step in this model.Comment: 26 pages, 9 figures. Published in Journal of Physics A: Mathematical
and Genera
Thermal, mechanical and microstructural analysis of concrete containing microencapsulated phase change materials
This paper studies the thermal, mechanical and microstructural aspects of concrete containing different amounts of microencapsulated phase change materials (PCMs). In addition, numerical simulation is carried out to study the potential application of PCM-modified concrete for reduction in summer surface temperature. It is shown that increasing PCM content in concrete led to lower thermal conductivity and an increase in the heat storage ability of concrete. However, the compressive and flexural strength of concrete significantly decreased. Microstructural analysis showed that PCMs appear to remain intact during mixing; however, PCM particles appear to fail by bursting under loading, creating hemispherical voids and crack initiation points as well as possible entrapped air behaviour. The result of numerical simulation revealed that reduction in summer concrete pavement surface temperature by several degrees was possible, with implications for reduction in concrete thermal stresses, shrinkage and urban heat island effect
Multifunctionality of Prostatic Acid Phosphatase in Prostate Cancer Pathogenesis
The role of human prostatic acid phosphatase (PAcP, P15309|PPAP_HUMAN) in prostate cancer was investigated using a new proteomics tool termed signal sequence swapping (replacement of domains from the native cleaved amino terminal signal sequence of secretory/membrane proteins with corresponding regions of functionally distinct signal sequence subtypes). This manipulation preferentially redirects proteins to different pathways of biogenesis at the endoplasmic reticulum (ER), magnifying normally difficult to detect subsets of the protein of interest. For PAcP, this technique reveals three forms identical in amino acid sequence but profoundly different in physiological functions, subcellular location, and biochemical properties. These three forms of PAcP can also occur with the wildtype PAcP signal sequence. Clinical specimens from patients with prostate cancer demonstrate that one form, termed PLPAcP, correlates with early prostate cancer. These findings confirm the analytical power of this method, implicate PLPAcP in prostate cancer pathogenesis, and suggest novel anticancer therapeutic strategies
Overview of the Kepler Science Processing Pipeline
The Kepler Mission Science Operations Center (SOC) performs several critical
functions including managing the ~156,000 target stars, associated target
tables, science data compression tables and parameters, as well as processing
the raw photometric data downlinked from the spacecraft each month. The raw
data are first calibrated at the pixel level to correct for bias, smear induced
by a shutterless readout, and other detector and electronic effects. A
background sky flux is estimated from ~4500 pixels on each of the 84 CCD
readout channels, and simple aperture photometry is performed on an optimal
aperture for each star. Ancillary engineering data and diagnostic information
extracted from the science data are used to remove systematic errors in the
flux time series that are correlated with these data prior to searching for
signatures of transiting planets with a wavelet-based, adaptive matched filter.
Stars with signatures exceeding 7.1 sigma are subjected to a suite of
statistical tests including an examination of each star's centroid motion to
reject false positives caused by background eclipsing binaries. Physical
parameters for each planetary candidate are fitted to the transit signature,
and signatures of additional transiting planets are sought in the residual
light curve. The pipeline is operational, finding planetary signatures and
providing robust eliminations of false positives.Comment: 8 pages, 3 figure
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