The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.

The quality of the chemical starting points for small-molecule drug discovery is a key factor in improving the likelihood of clinical success. In this article, experts from several organizations involved in drug discovery for malaria, tuberculosis and neglected tropical diseases present disease-specific criteria for hits and leads, and discuss the underlying rationale.

This paper describes the research methods required for the development and validation of a user interface for a wheelchair mounted manipulator for use by severely disabled persons. It explains the construction of the interface using tasks to define the user interface architecture. It outlines the experiments used to evaluate the user responses and draws conclusions about the effectiveness of the whole system. A systematic procedure is defined to obtain numerical estimates of the effectiveness of task analysis for individual use. This approach marries engineering procedures with a consideration of the human interaction. The prototype robot used several gesture recognition systems to achieve a better level of accessibility and usability than other robots used for rehabilitation at this time. Two different approaches to user interfaces were tested with different input devices.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cation-mediated cyclisation reactions of silyl enol ether-containing thioglycosides give bicyclic ketotetrahydrofurans. Cyclisation of an analogous 3-phenyl-2-propenyl ether-containing substrate gives an intermediate in the total synthesis of the higher-order sugar 2,3-dideoxy-d-manno-2-octulopyranosonic acid.

S-Glycosides possessing silyl enol ether groups tethered via an ether linkage undergo highly selective cation-mediated cyclisation reactions to give C-glycosidic ketotetrahydropyran-containing bicyclo[4.4.0] systems. These may be converted into a variety of monocyclic C-glycosides and their derivatives using oxidative and reductive tether-cleaving reactions.

A 14-step synthesis of the central tetrahydrofuran portion 4 of the elfamycin antibiotic aurodox is described, starting from the D-lyxose derivative 5. The key steps are template-directed intramolecular C-glycosidation by cation-mediated cyclisation of thioglycoside 6, and chelation-controlled addition of ethynylmagnesium bromide to aldehyde 8.

While climbing a properly set up aluminum extension ladder, a workman fell with the ladder after a crack completely penetrated one of the side rails. The crack initiated at a site which corresponded exactly with the location where the side rail normally rests on a steel ladder rack during transport. There are a number of recommended countermeasures in the ANSI ladder standards for preventing ladder damage from road shock and vehicle vibration including one which suggests securing the ladder at each support point. This bulletin demonstrates that the latter recommendation alone will prevent fretting damage and its associated loss of structural integrity.

Part 3 of this series of articles on PLC-controlled machinery (and the concluding one) continues in this issue of The Triodyne Safety Brief. In the first two parts of this series, which appeared in the June 1993 issue of the Safety Brief, Vol.8, No.3, and the February 1994, Vol.9, No.4 issue, the concept of the second industrial revoIution, based upon the mass production-short run idea, was developed. As a specific example, a large tri-axis transfer press was used as an embodiment of the idea and encompassing all of the necessary ancillary equipment required to support it. The history of the mass production-long run basis of American industry, extending back to the Civil War, but coming into its own during World War II, was explored. Additionally, the role of postwar global competitive forces in influencing the decision of American business to implement the mass production-short run concept was also analyzed. FIRE AND EXPLOSION: Triodyne Fire & Explosion Engineers, Inc. (Est. 1987) 2907 Butterfield Road Suite 120 Oak Brook, IL 60521-1176 (708) 573-7707 FAX: (708) 573-7731 Officers/Directors John A. Campbell Reed B. Varley Ralph L. Barnett S. Carl Uzgiris Chicago Office John A. Campbell Scott M. Howell Thomas H. Miller Kim R. Mniszewski Miami Office 1110 Brickell Avenue Suite 430 Miami, FL 33131-3135 (305) 374-4009 FAX: (305) 374-4011 Reed B. Varley Sheila Faith-Barry RECREATION ENGINEERING: Triodyne Recreation Engineering Inc. (Est. 1994) 5950 West Touhy Avenue Niles, IL 60714-4610 (708) 647-9882 FAX: (708) 647-0785 Officers/Directors Brian D. King Ralph L. Barnett S. Carl Uzgiris SAFETY RESEARCH: Institute for Advanced Safety Studies (Est. 1984) 5950 West Touhy Avenue Niles, IL 60714-4610 (708) 647-1101 Chairman of the Board Ralph L. Barnett Executive Director Leslie A. Savage Director of Research Thomas E. Waterman Information Services Sharon I. Meyer Senior Science Advisor Theodore Liber Assistant Research Engineer Peter J. Poczynok MANUFACTURING: Alliance Tool & Mfg. Inc. (Est. 1945) 91 East Wilcox Street Maywood, IL 60153-2397 (312) 261-1712 FAX: (708) 345-4004 Officers S. Carl Uzgiris Ralph L. Barnett General Manager Ramesh Gandhi Plant Manager Paul Schreiber Founders/Consultants Joseph Gansacz Albert Kanikula CONSTRUCTION: Triodyne-Wangler Construction Company Inc. (Est. 1993) 5950 West Touhy Avenue Niles, IL 60714-4610 (708) 677-4730 FAX: (708) 647-2047 Officers/ Directors/Managers Joel I. Barnett William A. Wangler Joseph Wangler Jon Strategos Ralph L. Barnett S. Carl Uzgiris CONSULTANTS: Richard M. Bilof, Ph.D. Electromagnetic Compatability R. A. Budenholzer, Ph.D. Power and Energy David W. Levinson, Ph.D. Senior Metallurgical Advisor James T. O'Donnell, Pharm.D. Pharmacology Steven R. Schmid, Ph.D. Food Processing Equipment

Confusion and misconceptions regarding the utility and safety of turf work trucks are addressed in this paper. Sources of this confusion include media stories of related vehicles and advertisements. The maneuverability, including both turning ability and traction performance, as well as lateralstability characteristics of threeand four-wheeled turf work trucks are evaluated based on experimental tests and mathematical models. Experiments with the three most popular heavy-duty turf work trucks from Cushman® and Toro® show that the three-wheeled model maintains a distinct advantage over the four-wheeled models with respect to maneuverability in tight spaces as measured in clearance-circle tests. Tractionperformance tests with these vehicles show there to be considerable variations in traction performance between vehicles, test conditions, and loading states. The analyses of the lateral-stability characteristics of threeand four-wheeled turf work trucks, using a mathematical model, indicate that the optimum four-wheeled vehicle is more laterally stable than the three wheeler for equal track widths. However, among vehicles of equal clearancecircle performance, the optimum three-wheeled vehicle stability surpasses that of the four wheeler. This paper continues with the analysis of the effects of a simple load on threeand four-wheeled vehicle stability which shows qualitatively different effects of loading on the two vehicle configurations. Finally, this paper evaluates the need for and implementation of a rollover protective structure (ROPS) system. Among the conclusions reached is that both threeand four-wheeled turf work trucks are required to achieve all of the performance goals found in the workplace.

Occasionally, vehicles topple off of structurally sound automobile lifts, even when they are properly supported at their lift points. This happens with a family of lifts that use four arms to position lifting pads under the vehicle chassis. The arms operate in a horizontal plane and are positioned by swinging and telescoping. Gravity loading of the pads and the attendant horizontal friction resistance cannot be relied upon to maintain the set-up position of the pads. There is a non-obvious structural phenomena called hyperstatic behavior that may easily lead to minimal, or even zero, pad loading with the attendant loss of resistance to horizontal pad movement. Unless otherwise restrained, the bumping and jostling associated with vehicle maintenance can produce random forces that will push a pad from beneath the vehicle. The resulting three-point support almost always leads to toppling of the vehicle from the lift.

Compliance or noncompliance with a sound safety code or standard is currently the most rational way of judging whether a product or system is sufficiently safe. Many such codes and standards specify minimum numerical criteria such as loading, tilt angle and duration time by which compliance may be judged. Usually it is more valuable to make judgments based on quantitative test data as opposed to meeting minimum criteria. For example, a lawn and garden tractor will remain stable when tilted laterally to 28.7° compared with the go/no-go minimum specification of 20°. This paper illustrates the richness of quantification for a number of different products including hook-on high chairs, grinding wheels, structural members and smoke detectors.

On May 4, 1988, a fire occurred in a large ammonium perchlorate (AP) plant located in Henderson, Nevada. The fire quickly spread through most of the facility by means of thermal radiation, fire brands, a continuous (linear) source of fuel and some natural self-propelled missiles. Two large explosions occurred during the fire, each on the order of a few hundred tons energy equivalent of TNT, claiming two lives, injuring 372 people, and damaging plant buildings as well as buildings in nearby residential areas. During the early stages of the plant fire, a television tower maintenance crew atop a nearby mountain noticed the event and recorded most of it on videotape. The video record is unusual, spectacular, and a rare opportunity in fire/explosion investigation. It shows details of the rapid plant fire spread sequence, much of which occurred too quickly to be accurately recorded by any other means. The videotape permitted advanced investigative fire reconstruction techniques, such as super imposing CAD outlines of the plant on the video records, using the same perspective. Various other engineering analyses were conducted for the effort as well. Timeline analyses (from witness and other accounts) aided in determining the complex sequence of events leading up to ignition, as well as the sequence of flame spread. Thermal radiation heat transfer calculations aided in determination and confirmation of flame spread theories. Explosion dynamics estimates aided in determining the locations of the initial small explosions and estimating the amount of product involved in the large explosions. Possible causes of the accident are listed, though the official cause is still undetermined. Conclusions are listed regarding major factors involved in the ignition and extreme rate of fire spread. ENVIRONMENTAL ENGINEERING: Triodyne Environmental Engineering, Inc. (Est. 1989) 5950 West Touhy Avenue Niles, IL 60714-4610 (708) 647-6748 FAX: (708) 647-2047 Officers/Directors Gary M. Hutter Ralph L. Barnett S. Carl Uzgiris Engineering/Science John P. Bederka, Jr. Richard Gullickson Diane Moshman James T. O'Donnell William D. Sheridan Audrone M. Stake Library/Research Services Lucinda Fuller Shelley Hamilton RECREATION ENGINEERING: Triodyne Recreation Engineering Inc. (Est. 1994) 5950 West Touhy Avenue Niles, IL 60714-4610 (708) 647-9882 FAX: (708) 647-0785 Officers/Directors Brian D. King Jeffery W. Abendshien Ralph L. Barnett S. Carl Uzgiris SAFETY RESEARCH: Institute for Advanced Safety Studies (Est. 1984) 5950 West Touhy Avenue Niles, IL 60714-4610 (708) 647-1101 Chairman of the Board Ralph L. Barnett Executive Director Leslie A. Savage Director of Research James T. Semrau Information Services Sharon I. Meyer Senior Science Advisor Theodore Liber Assistant Research Engineer Peter J. Poczynok MANUFACTURING: Alliance Tool & Mfg. Inc. (Est. 1945) 91 East Wilcox Street Maywood, IL 60153-2397 (312) 261-1712 FAX: (708) 345-4004 Officers S. Carl Uzgiris Ralph L. Barnett General Manager Ramesh Gandhi Plant Manager Paul Schreiber Founders/Consultants Joseph Gansacz Albert Kanikula CONSTRUCTION: Triodyne-Wangler Construction Company Inc. (Est. 1993) 5950 West Touhy Avenue Niles, IL 60714-4610 (708) 677-4730 FAX: (708) 647-2047 Officers/Directors/Managers Joel I. Barnett William A. Wangler Joseph Wangler Ralph L. Barnett S. Carl Uzgiris CONSULTANTS: Richard M. Bilof, Ph.D. Electromagnetic Compatability R. A. Budenholzer, Ph.D. Power and Energy David W. Levinson, Ph.D. Senior Metallurgical Advisor James T. O'Donnell, Pharm.D. Pharmacology Steven R. Schmid, Ph.D. Food Processing Equipment MECHANICAL ENGINEERING: Triodyne Inc. (Est. 1969) Officers Ralph L. Barnett Dolores Gildin S. Carl Uzgiris Mechanical Engineering Dennis B. Brickman Kenneth L. d'Entremont Michael A. Dilich Christopher W. Ferrone Claudine P. Giebs Suzanne A. Glowiak John M. Goebelbecker Crispin Hales Gary M. Hutter Brian D. King Dror Kopernik Woodrow Nelson R. Kevin Smith Harry R. Smith William G. Switalski Paul Terronez Andrew H. Tudor James R. Wingfield Library Services Sharon I. Meyer Lisa Beckers Betty Bellows Lucinda Fuller Maureen Gilligan Jan A. King Norene Kramer Molly Kravetz Florence Lasky Kimberly Last Neil Miller Jackie Schwartz Marta Thalos Peter Warner Information Products Expert Transcript Center (ETC) Lisa Beckers Glenn Werner Contract Services Sharon I. Meyer Graphic Communications and Video Services Mary A. Misiewicz Charles D'Eccliss Alison Newberry Anthony Provenzano Robin Stone Christina Timmins Lynn Wallace-Mills Thomas E. Zabinski Training and Editorial Services Paula L. Barnett Model Laboratory 2721 Alison Lane Wilmette, IL 60091-2101 Robert Kaplan Bill Brown Mario Visocnik Vehicle Laboratory Charles Sinkovits Patrick M. Brinckerhoff Photographic Laboratory 7903 Beckwith Road Morton Grove, IL 60053 Larry Good Business Systems Maryalyce Skree Sharon L. Mathews Chris Ann Gonatas Karen Kotsovetis Vicki Lipinski Special Projects John K. Burge Michael F. Mulhall FIRE AND EXPLOSION: Triodyne Fire & Explosion Engineers, Inc. (Est. 1987) 2907 Butterfield Road Suite 120 Oak Brook, IL 60521-1176 (708) 573-7707 FAX: (708) 573-7731 Officers/Directors John A. Campbell Reed B. Varley Ralph L. Barnett S. Carl Uzgiris Chicago Office John A. Campbell Scott M. Howell Thomas H. Miller Kim R. Mniszewski Miami Office 1110 Brickell Avenue Suite 430 Miami, FL 33131-3135 (305) 374-4009 FAX: (305) 374-4011 Reed B. Varley Sheila Faith-Barry * Reprinted with the permission of the Society of Fire Protection Engineers: Journal of Fire Protection Engineering vol. 6, no. 2 (1994): 63-78. ** Fire Protection Engineer, Triodyne Fire and Explosion Engineers Inc., Oak Brook, Illinois.