Design of Allosteric Stimulators of the Hsp90 ATPase as New Anticancer Leads

Allosteric compounds that stimulate Hsp90 adenosine triphosphatase (ATPase) activity were rationally designed, showing anticancer potencies in the low micromolar to nanomolar range. In parallel, the mode of action of these compounds was clarified and a quantitative model that links the dynamic ligand-protein cross-talk to observed cellular and in vitro activities was developed. The results support the potential of using dynamics-based approaches to develop original mechanism-based cancer therapeutics

Aerodynamics of aero-engine installation

This paper describes current progress in the development of methods to assess aero-engine airframe installation effects. The aerodynamic characteristics of isolated intakes, a typical transonic transport aircraft as well as a combination of a through-flow nacelle and aircraft configuration have been evaluated. The validation task for an isolated engine nacelle is carried out with concern for the accuracy in the assessment of intake performance descriptors such as mass flow capture ratio and drag rise Mach number. The necessary mesh and modelling requirements to simulate the nacelle aerodynamics are determined. Furthermore, the validation of the numerical model for the aircraft is performed as an extension of work that has been carried out under previous drag prediction research programmes. The validation of the aircraft model has been extended to include the geometry with through flow nacelles. Finally, the assessment of the mutual impact of the through flow nacelle and aircraft aerodynamics was performed. The drag and lift coefficient breakdown has been presented in order to identify the component sources of the drag associated with the engine installation. The paper concludes with an assessment of installation drag for through-flow nacelles and the determination of aerodynamic interference between the nacelle and the aircraft

Quaternary geology of the Northern Great Plains

The Great Plains physiographic province lies east of the Rocky Mountains and extends from southern Alberta and Saskatchewan nearly to the United States-Mexico border. This chapter covers only the northern part of the unglaciated portion of this huge region, from Oklahoma almost to the United StatesCanada border, a portion that herein will be referred to simply as the Northern Great Plains (Fig. 1). This region is in the rain shadow of the Rocky Mountains. Isoheyets are roughly longitudinal, and mean annual precipitation decreases from about 750 mm at the southeastern margin to less than 380 mm in the western and northern parts (Fig. 2). Winters typically are cold with relatively little precipitation, mostly as snow; summers are hot with increased precipitation, chiefly associated with movement of Pacific and Arctic air masses into warm, humid air masses from the Gulf of Mexico. Vegetation is almost wholly prairie grassland, due to the semiarid, markedly seasonal climate. The Northern Great Plains is a large region of generally low relief sloping eastward from the Rocky Mountains toward the Missouri and Mississippi Rivers. Its basic bedrock structure is a broad syncline, punctuated by the Black Hills and a few smaller uplifts, and by structural basins such as the Williston, Powder River, and Denver-Julesburg Basins (Fig. 3). Its surface bedrock is chiefly Cretaceous and Tertiary sediments, with small areas of older rocks in the Black Hills, central Montana, and eastern parts of Wyoming, Kansas, and Oklahoma. During the Laramide orogeny (latest Cretaceous through Eocene), while the Rocky Mountains and Black Hills were rising, synorogenic sediments (frequently with large amounts of volcanic ash from volcanic centers in the Rocky Mountains) were deposited in the subsiding Denver-Julesburg, Powder River, and other basins. From Oligocene to Miocene time, sedimentation generally slowed with declining tectonism and volcanism in the Rocky Mountains. However, since the later Miocene, epeirogenic uplift, probably associated with the East Pacific Rise, affected the Great Plains and particularly the Rocky Mountains. During the last 10 m.y. the Rocky Mountain front has risen 1.5 to 2 km, and the eastern margin of the Great Plains 100 to 500 m (Gable and Hatton, 1983), with half to one-quarter of these amounts during the last 5 m.y. Thus, during the later Miocene the Great Plains became a huge aggrading piedmont sloping gently eastward from the Rocky Mountains and Black Hills, with generally eastward drainage, on which the Ogallala Formation and equivalents was deposited. The Ogallala underlies the High Plains Surface, the highest and oldest geomorphic surface preserved in this region. It has been completely eroded along some parts of the western margin of the region (e.g., the Colorado Piedmont), but eastward, it (and its equivalents, such as the Flaxville gravels in Montana) locally is preserved as caprock or buried by Quaternary sediments (Alden, 1924, 1932; Howard, 1960; Stanley, 1971, 1976; Pearl, 1971; Scott, 1982; Corner and Diffendal, 1983; Diffendal and Corner, 1984; Swinehart and others, 1985; Aber, 1985). During the Pliocene, regional aggradation slowly changed to dissection by the principal rivers. In the western part of the region the rivers flowed eastward, but the continental drainage divide Figure 3. Major bedrock structures of the Northern Great Plains. extended northeast from the Black Hills through central South Dakota, far south of its present position. The ancestral upper Missouri, Little Missouri, Yellowstone, and Cheyenne Rivers drained northeast to Hudson Bay, whereas the ancestral White, Platte, and Arkansas Rivers went to the Gulf of Mexico (Fig 4A). Their courses are marked by scattered surface and subsurface gravel remnants; in Montana and North Dakota, deposits of the preglacial Missouri River and its tributaries are buried deeply beneath glacial and other sediments (Howard, 1960; Bluemle, 1972)

Abnormal T-cell phenotype in episodic angioedema with hypereosinophilia (Gleich's syndrome): frequency, clinical implication and prognosis

BACKGROUND: Episodic Angioedema with eosinophilia (EAE, Gleich\u27s syndrome) is a rare disorder consisting of recurrent episodes of angioedema, hypereosinophilia and frequent elevated serum Immunoglobin M. METHODS: We conducted a retrospective multicenter nationwide study regarding the clinical spectrum and therapeutic management of patients with EAE in France. RESULTS: Thirty patients were included with a median age at diagnosis of 41 years [5-84]. The median duration of each crisis was 5.5 days [1-90] with swelling affecting mainly the face and the upper limbs. Total serum IgM levels were increased in 20 patients (67%). Abnormal T-cell immunophenotypes were detected in 12 patients (40%) among which 5 (17%) showed evidence of clonal TCR γ gene rearrangement. Median follow-up duration was 53 months [31-99]. The presence of an abnormal T-cell population was the sole factor associated with a shorter time to flare (hazard ratio 4.15 [CI 95% 1.18-14.66; p=0.02). At last follow-up, 3 patients (10%) were able to withdraw all treatments and 11 (37%) were in clinical and biological remission with less than 10 mg of daily prednisone. CONCLUSION: EAE is a heterogeneous condition that encompasses several disease forms. Although patients usually respond well to glucocorticoids, those with evidence of abnormal T-cell phenotype have a shorter time to flare

Reactivity of Biarylazacyclooctynones in Copper-Free Click Chemistry

The 1,3-dipolar cycloaddition of cyclooctynes with azides, also called "copper-free click chemistry", is a bioorthogonal reaction with widespread applications in biological discovery. The kinetics of this reaction are of paramount importance for studies of dynamic processes, particularly in living subjects. Here we performed a systematic analysis of the effects of strain and electronics on the reactivity of cyclooctynes with azides through both experimental measurements and computational studies using a density functional theory (DFT) distortion/interaction transition state model. In particular, we focused on biarylazacyclooctynone (BARAC) because it reacts with azides faster than any other reported cyclooctyne and its modular synthesis facilitated rapid access to analogues. We found that substituents on BARAC's aryl rings can alter the calculated transition state interaction energy of the cycloaddition through electronic effects or the calculated distortion energy through steric effects. Experimental data confirmed that electronic perturbation of BARAC's aryl rings has a modest effect on reaction rate, whereas steric hindrance in the transition state can significantly retard the reaction. Drawing on these results, we analyzed the relationship between alkyne bond angles, which we determined using X-ray crystallography, and reactivity, quantified by experimental second-order rate constants, for a range of cyclooctynes. Our results suggest a correlation between decreased alkyne bond angle and increased cyclooctyne reactivity. Finally, we obtained structural and computational data that revealed the relationship between the conformation of BARAC's central lactam and compound reactivity. Collectively, these results indicate that the distortion/interaction model combined with bond angle analysis will enable predictions of cyclooctyne reactivity and the rational design of new reagents for copper-free click chemistry