N‐Arylsulfonyl Indolines as Retinoic Acid Receptor‐Related Orphan Receptor γ (RORγ) Agonists

The nuclear retinoic acid receptor‐related orphan receptor γ (RORγ; NR1F3) is a key regulator of inflammatory gene programs involved in T helper 17 (T_H17) cell proliferation. As such, synthetic small‐molecule repressors (inverse agonists) targeting RORγ have been extensively studied for their potential as therapeutic agents for various autoimmune diseases. Alternatively, enhancing T_H17 cell proliferation through activation (agonism) of RORγ may boost an immune response, thereby offering a potentially new approach in cancer immunotherapy. Herein we describe the development of N‐arylsulfonyl indolines as RORγ agonists. Structure–activity studies reveal a critical linker region in these molecules as the major determinant for agonism. Hydrogen/deuterium exchange coupled to mass spectrometry (HDX‐MS) analysis of RORγ–ligand complexes help rationalize the observed results.     

Estimation of Width and Depth of the Wetted Soil Volume Under a Surface Emitter,Considering Root Water-Uptake and Evaporation

A cylindrical flow model that describes local infiltration from a surface point source, by incorporating evaporation and water extraction by roots, was used to obtain numerical results that were the base for the development and testing of an empirical method for determining the surface and vertical components of the wetting front. The implementation of the mathematical model took place against two of the twelve USDA soil classes, using three water application rates for each one. The empirical methodology consisted of two simple, time dependent empirical relationships: a power law for the stage of the infiltration, which was applied in both directions and a polynomial for the stage after the end of the irrigation, applied only for the vertical component, to account for percolation losses. The statistical criteria used for the evaluation of the method showed good agreement between the numerical results and the values calculated by the empirical relationships. Based on the limited availability of necessary experimental data for detailed analysis of multidimensional transient infiltration, the introduction of such an empirical model, as a design tool for trickle irrigation systems, may contribute to the selection of the optimum application rate and lateral spacing.     

Output feedback eigenstructure assignment using a new reduced orthogonality condition

This paper presents a new method of output feedback eigenstructure assignment. A new, reduced orthogonality condition is derived which is less restrictive on the design degrees of freedom than others in the literature. From this a novel, general formulation for the gain matrix is admitted which utilizes a two stage design process. In the first stage, a subset of desired eigenvectors is assigned, either left or right. In the second stage, a dual set is assigned which adheres to the necessary and sufficient conditions for output feedback eigenstructure assignment proved earlier in the paper. A numerical example is presented to illustrate the whole procedure.     

The association between price of regular-grade gasoline and injury and mortality rates among occupants involved in motorcycle- and automobile-related motor vehicle collisions

Motorcyclists have been reported to be more likely to die in a motor vehicle collision (MVC) than automobile occupants. With the recent increase in the pump price of gasoline, it has been reported that people are switching to motorcycles as main modes of transportation. This study evaluated the association between motor vehicle collision-related injury and mortality rates and increases in gasoline prices for occupants of automobiles and riders of motorcycles.There were an estimated 1,270,512 motorcycle MVC and 238,390,853 automobile MVC involved occupants in the U.S. from 1992 to 2007. Higher gasoline prices were associated with increased motorcycle-related injuries and deaths; however, this association no longer remained after accounting for changes in the number of registered vehicles.The current study observed that, while the number of injuries and fatalities in motorcycle-related MVCs increase with increasing gasoline price, rates remained largely unchanged. This suggests that the observed increase in motorcycle-related injuries and fatalities with increasing gasoline price is more a factor of the number of motorcycles on the road rather than operator characteristics.     

Can Brazil replace 5% of the 2025 gasoline world demand with ethanol?

Increasing use of petroleum, coupled with concern for global warming, demands the development and institution of CO₂ reducing, non-fossil fuel-based alternative energy-generating strategies. Ethanol is a potential alternative, particularly when produced in a sustainable way as is envisioned for sugarcane in Brazil. We consider the expansion of sugarcane-derived ethanol to displace 5% of projected gasoline use worldwide in 2025. With existing technology, 21 million hectares of land will be required to produce the necessary ethanol. This is less than 7% of current Brazilian agricultural land and equivalent to current soybean land use. New production lands come from pasture made available through improving pasture management in the cattle industry. With the continued introduction of new cane varieties (annual yield increases of about 1.6%) and new ethanol production technologies, namely the hydrolysis of bagasse to sugars for ethanol production and sugarcane trash collection providing renewable process energy production, this could reduce these modest land requirements by 29–38%.     

Cryogenic probe 13C NMR spectroscopy of urine for metabonomic studies

Cryogenic probe technology can significantly compensate for the inherently low sensitivity of natural abundance 13C NMR spectroscopy. This now permits its routine use in NMR spectroscopy of biofluids, such as urine or plasma, with acquisition times that enable a high throughput of samples. Metabonomic studies often generate numerous samples in order to characterize fully the time-dependent biochemical response to stimuli, but until now, they have been largely conducted using 1H NMR spectroscopy because of its high sensitivity and hence efficient data acquisition. Here, we demonstrate that information-rich 13C NMR spectra of rat urine can be obtained using appropriately short acquisition times suitable for biochemical samples when using a cryogenic probe. Furthermore, these data were amenable to automated pattern recognition analysis, which produced a profile of the metabolic response to the model hepatotoxin hydrazine that was consistent with earlier studies. Thus, a new source of detailed and complementary information is available to metabonomics using cryogenic probe 13C NMR spectroscopy.     

A note on deciding controllability in pushdown systems

Consider an event alphabet /spl Sigma/. The supervisory control theory of Ramadge and Wonham asks the question, given a plant model G, with language K L/sub M/(G)/spl sube//spl Sigma//sup */ and another language K/spl sube/ L/sub M/(G), is there a supervisor /spl psi/ such that L/sub M/(/spl psi//G)=K. Ramadge and Wonham showed that a necessary condition for this to be true is the so-called controllability of K with respect to L/sub M/(G). They showed that when G is a finite state automaton and K is a regular language (also generated by a finite state automaton), then the controllability property was decidable for K. The class of languages generated by pushdown automata properly includes the regular languages. They are accepted by finite state machines coupled with pushdown stack memory. This makes them interesting candidates as supervisory languages, since the supervisor will have nonfinite memory. In this note, we show the following: i) If S is a specification given by a deterministic pushdown automaton and L is generated by a finite state machine, then there is an algorithm to decide whether K=S/spl cap/L is controllable with respect to L. ii) It is undecidable for an arbitrary specification S generated by a nondeterministic pushdown automaton and plant language L generated by a finite state machine whether K=S/spl cap/L is controllable with respect to L.     

Replace, refurbish, or retain? Evaluating aging electrical systems and equipment

Many electrical facilities were constructed or experienced major expansions in the 1950s and 1960s. We are now having to deal with electrical switchgear and systems that are 40 to 50 years old. Depending upon the environment and application of the equipment, they may be at or near the end of their useful lives. In order to make an objective evaluation of the equipment's condition and develop a forward plan for operation, reconditioning, or replacement, a detailed application guide for condition assessment of their aged medium-voltage (MV) switchgear was developed and described in this article. Over the past 40 to 50 years, the equipment has not only aged, but the electrical systems have often expanded to meet the needs of future growth and expansion. This growth has sometimes followed a well-planned strategy based on up-front conceptual studies integrated into long range plans. On other occasions, this growth has been achieved by adding on to existing facilities in an often haphazard manner, or by duplicating existing facilities, equipment, and designs. For a number of reasons, the reliability of our electrical facilities and related losses due to power failures may not be meeting our management's expectations. This article describes a process developed to model an electrical system and calculate system reliability and related financial risks based on the actual system components and process unit cost impacts.     

Qualitative models of seat discomfort including static and dynamic factors

Judgements of overall seating comfort in dynamic conditions sometimes correlate better with the static characteristics of a seat than with measures of the dynamic environment. This study developed qualitative models of overall seat discomfort to include both static and dynamic seat characteristics. A dynamic factor that reflected how vibration discomfort increased as vibration magnitude increased was combined with a static seat factor which reflected seating comfort without vibration. The ability of the model to predict the relative and overall importance of dynamic and static seat characteristics on comfort was tested in two experiments. A paired comparison experiment, using four polyurethane foam cushions (50, 70, 100, 120 mm thick), provided different static and dynamic comfort when 12 subjects were exposed to one-third octave band random vertical vibration with centre frequencies of 2.5 and 5.5 Hz, at magnitudes of 0.00, 0.25 and 0.50 m x s(-2) rms measured beneath the foam samples. Subject judgements of the relative discomfort of the different conditions depended on both static and dynamic characteristics in a manner consistent with the model. The effect of static and dynamic seat factors on overall seat discomfort was investigated by magnitude estimation using three foam cushions (of different hardness) and a rigid wooden seat at six vibration magnitudes with 20 subjects. Static seat factors (i.e. cushion stiffness) affected the manner in which vibration influenced the overall discomfort: cushions with lower stiffness were more comfortable and more sensitive to changes in vibration magnitude than those with higher stiffness. The experiments confirm that judgements of overall seat discomfort can be affected by both the static and dynamic characteristics of a seat, with the effect depending on vibration magnitude: when vibration magnitude was low, discomfort was dominated by static seat factors; as the vibration magnitude increased, discomfort became dominated by dynamic factors.