Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

Similarities and differences between male and female novice designers on color‐concept associations for warnings,action required,and signs and equipment status messages

This research examined the male and female novice designers toward color associations for the concepts used for ‘warnings’, ‘action required’, and ‘signs and equipment status’ through a questionnaire‐based study. A total of 178 Hong Kong Chinese final year undergraduate design students (89 males and 89 females) participated in the study. The test used required the participants to indicate their choice of one of nine colors to associations with each of 38 concepts in a color‐concept table, so that any one color could be associated with any one of the concepts. For both male and female groups of novice designers, chi‐square tests revealed a strong color association for each concept tested in this study (P < .05). The results showed males and females agreed on some color‐concept association stereotypes which were therefore gender neutral. The male and female novice designers had the same color associations and similar levels of stereotype strengths for 21 concepts. The nine strongest and therefore most useful color‐concept association stereotypes for both male and female novice designers were: red‐danger, red‐fire, red‐hot, red‐stop, red‐emergency, red‐error, blue‐cold, blue‐male, and green‐exit. However, the male and female novice designers had different color association stereotypes for the standby (green vs. yellow), emergency exit (green vs. red), and toxic (purple vs. black) concepts, and the strengths of the 14 remaining associations for both groups were not at equivalent levels. Overall, it is anticipated that the findings of this study will act as a useful reference for novice designers and other design practitioners to optimize color coding in the design of ‘warnings’, ‘action required’, and ‘signs and equipment status’ messages.     

Within-class multimodal classification

Multimedia Tools and Applications - In many real-world classification problems there exist multiple subclasses (or clusters) within a class; in other words, the underlying data distribution is...     

Analysis of phosphorus removal and anaerobic selector performance in a full-scale activated sludge process in Singapore.

This paper analyses the performance of the anaerobic selector (A/O process) in a full-scale activated sludge process receiving mostly industrial sewage discharge (> 60%) in Singapore. In addition to the sludge settleability, enhanced biological phosphorus removal (EBPR) was studied. The sludge volume index (SVI) reduced from 200 to 80 ml g(-1) and foaming was suppressed significantly, indicating the effectiveness of the anaerobic selector in improving sludge settleability. The phosphorus removal efficiency was 66%, and 7.5 mg HAc-COD was consumed per mg PO4(3-) -P removed. In the anaerobic compartment, 31% of the SCOD and 73% of the acetic acid in the settled sewage were removed with PO4(3-) -P release of 14.1 mg PO4(3-)-P l(-1). The linear correlation between PO4(3-) -P release in the anaerobic compartment and PO4(3-) -P uptake in the aerobic compartment indicates that there is about 0.8 mg PO4(3-) -P release in the anaerobic compartment per mg PO34(3-) -P uptake in the aerobic compartment. The fates of volatile fatty acids (VFAs) and its short chain acids (SCAs) in the process were studied and discussed.     

Using an integrated process of data and modeling in HRA

The paper describes an approach taken to estimate the probabilities of failure associated with various railroad tasks to prevent accidents (principally collisions and derailments). These probabilities were estimated using an expert elicitation process that used partially relevant data available from a variety of databases and that were filtered and scaled to make them more directly relevant to the analyses being performed. Extensive qualitative studies were performed prior to the elicitation process to identify relevant contexts under which the tasks can be performed.     

Generalized multiuser orthogonal space-division multiplexing

This paper addresses the problem of performing orthogonal space-division multiplexing (OSDM) for downlink, point-to-multipoint communications when multiple antennas are utilized at the base station (BS) and (optionally) all mobile stations (MS). Based on a closed-form antenna weight solution for single-user multiple-input multiple-output communications in the presence of other receiver points, we devise an iterative algorithm that finds the multiuser antenna weights for OSDM in downlink or broadcast channels. Upon convergence, each mobile user will receive only the desired activated spatial modes with no cochannel interference. Necessary and sufficient conditions for the existence of OSDM among the number of mobile users, the number of transmit antennas at the BS, and the number of receive antennas at the MS, are also derived. The assumption for the proposed method is that the BS knows the channels for all MS's and that the channel dynamics are quasi-stationary.     

The effects of nonlocal impact ionization on the speed of avalanche photodiodes

The nonlocal enhancement in the velocities of charge carriers to ionization is shown to outweigh the opposing effects of dead space, increasing the avalanche speed of short avalanche photodiodes (APDs) over the predictions of a conventional local model which ignores both of these effects. The trends in the measured gain-bandwidth product of two short InAlAs APDs reported in the literature support this result. Relatively large speed benefits are predicted to result from further small reductions in the lengths of short multiplication regions.     

Expanding the analytical potential of channel locational probability maps using cellular statistics

The planimetric shifts in channel location of large alluvial rivers are a critical component in the creation of diverse structures and functions in riverine habitats. Engineered management schemes must also compensate for this type of channel change to protect resources and maintain navigation channels. The stability of the Lower Mississippi River channel was assessed through an analysis of historical records of channel position produced and archived by the United States Army Corps of Engineers. Channel location was recorded for the years 1765, 1820, 1881, 1915, 1930, 1937, 1960 and 1970. Channel stability was measured by two introduced metrics on a cell‐by‐cell basis: (1) the standard deviation of Euclidean distance to a channel cell for the entire period of record, and (2) the rate of Euclidean distance change between years in the period of record. At a coarse spatial scale, channel instability increased in the downstream direction. The variability of channel stability also increased in the downstream direction. Analysis of this variability identified alternating areas of high and low stability occurring with greater frequency as distance downstream increased. These findings are validated by past studies of channel stability along the Lower Mississippi River. As a result, the proposed metrics provide a consistent, quantitative, efficient and cost‐effective means of identifying areas of channel instability at several spatial scales. Copyright © 2006 John Wiley & Sons, Ltd.