Exploring N-acyl-4-azatetracyclo[5.3.2.0.0]dodec-11-enes as 11β-HSD1 Inhibitors

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11β-HSD1. In continuation of our efforts to discover potent and selective 11β-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11β-HSD1, although with low selectivity over the isoenzyme 11β-HSD2, and poor microsomal stability

Estimating Probability Distributions from Complex Models with Bifurcations: The Case of Ocean Circulation Collapse

Abstract in HTML and technical report in PDF available on the Massachusetts Institute of Technology Joint Program on the Science and Policy of Global Change website (http://mit.edu/globalchange/www/).Studying the uncertainty in computationally expensive models has required the development of specialized methods, including alternative sampling techniques and response surface approaches. However, existing techniques for response surface development break down when the model being studied exhibits discontinuities or bifurcations. One uncertain variable that exhibits this behavior is the thermohaline circulation (THC) as modeled in three-dimensional general circulation models. This is a critical uncertainty for climate change policy studies. We investigate the development of a response surface for studying uncertainty in THC using the Deterministic Equivalent Modeling Method, a stochastic technique using expansions in orthogonal polynomials. We show that this approach is unable to reasonably approximate the model response. We demonstrate an alternative representation that accurately simulates the model’s response, using a basis function with properties similar to the model’s response over the uncertain parameter space. This indicates useful directions for future methodological improvements.This research was supported in part by the Methods and Models for Integrated Assessments Program of the National Science Foundation, Grant ATM-9909139, by the Office of Science (BER), U.S. Department of Energy, Grant Nos. DE-FG02-02ER63468 and DE-FG02-93ER61677, and by the MIT Joint Program on the Science and Policy of Global Change (JPSPGC)

Relative Roles of Climate Sensitivity and Forcing in Defining the Ocean Circulation Response to Climate Change

Abstract in HTML and technical report in PDF available on the Massachusetts Institute of Technology Joint Program on the Science and Policy of Global Change website (http://mit.edu/globalchange/www/).The response of the ocean’s meridional overturning circulation (MOC) to increased greenhouse gas forcing is examined using a coupled model of intermediate complexity, including a dynamic 3D ocean subcomponent. Parameters are the increase in CO2 forcing (with stabilization after a specified time interval) and the model’s climate sensitivity. In this model, the cessation of deep sinking in the north “Atlantic” (hereinafter, a “collapse”), as indicated by changes in the MOC, behaves like a simple bifurcation. The final surface air temperature (SAT) change, which is closely predicted by the product of the radiative forcing and the climate sensitivity, determines whether a collapse occurs. The initial transient response in SAT is largely a function of the forcing increase, with higher sensitivity runs exhibiting delayed behavior; accordingly, high CO2-low sensitivity scenarios can be assessed as a recovering or collapsing circulation shortly after stabilization, whereas low CO2-high sensitivity scenarios require several hundred additional years to make such a determination. We also systemically examine how the rate of forcing, for a given CO2 stabilization, affects the ocean response. In contrast with previous studies based on results using simpler ocean models, we find that except for a narrow range of marginally stable to marginally unstable scenarios, the forcing rate has little impact on whether the run collapses or recovers. In this narrow range, however, forcing increases on a time scale of slow ocean advective processes results in weaker declines in overturning strength and can permit a run to recover that would otherwise collapse.This research was supported in part by the Methods and Models for Integrated Assessments Program of the National Science Foundation, Grant ATM-9909139, by the Office of Science (BER), U.S. Department of Energy, Grant No. DE-FG02-93ER61677, and by the MIT Joint Program on the Science and Policy of Global Change (JPSPGC)

Suicide inhibition of alpha-oxamine synthases:structures of the covalent adducts of 8-amino-7-oxononanoate synthase with trifluoroalanine

The suicide inhibition of the α-oxamine synthases by the substrate analog, L-trifluoroalanine was investigated. The inhibition resulted in the formation of a complex with loss of all three fluorine atoms. Decarboxylation and loss of fluoride occurred immediately after aldimine formation. The inherent flexibility could allow the difluorinated intermediate complex to adopt a suitable conformation. Decarboxylation in the normal mechanism occurs after formation of the ketoacid intermediate.link_to_subscribed_fulltex

Cognitive and disease-modifying effects of 11ß-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer's disease

Chronic exposure to elevated levels of glucocorticoids has been linked to age-related cognitive decline and may play a role in Alzheimer's disease. In the brain, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies intracellular glucocorticoid levels. We show that short-term treatment of aged, cognitively impaired C57BL/6 mice with the potent and selective 11β-HSD1 inhibitor UE2316 improves memory, including after intracerebroventricular drug administration to the central nervous system alone. In the Tg2576 mouse model of Alzheimer's disease, UE2316 treatment of mice aged 14 months for 4 weeks also decreased the number of β-amyloid (Aβ) plaques in the cerebral cortex, associated with a selective increase in local insulin-degrading enzyme (involved in Aβ breakdown and known to be glucocorticoid regulated). Chronic treatment of young Tg2576 mice with UE2316 for up to 13 months prevented cognitive decline but did not prevent Aβ plaque formation. We conclude that reducing glucocorticoid regeneration in the brain improves cognition independently of reduced Aβ plaque pathology and that 11β-HSD1 inhibitors have potential as cognitive enhancers in age-associated memory impairment and Alzheimer's dementia

Optical Spectroscopy of Galactic Cirrus Clouds: Extended Red Emission in the Diffuse Interstellar Medium

We present initial results from the first optical spectroscopic survey of high latitude Galactic cirrus clouds. The observed shape of the cirrus spectrum does not agree with that of scattered ambient Galactic starlight. This mismatch can be explained by the presence of Extended Red Emission (ERE) in the diffuse interstellar medium, as found in many other astronomical objects, probably caused by photoluminescence of hydrocarbons. The integrated ERE intensity, I_ERE \approx 1.2 x 10^{-5} erg s^{-1} cm^{-2} sr^{-1}, is roughly a third of the scattered light intensity, consistent with recent color measurements of diffuse Galactic light. The peak of the cirrus ERE (lambda_{0} \sim 6000 AA) is shifted towards short (bluer) wavelengths compared to the ERE in sources excited by intense ultraviolet radiation, such as HII regions (lambda_{0} sim 8000 AA); such a trend is seen in laboratory experiments on hydrogenated amorphous carbon films.Comment: 7 pages, 2 figures. Accepted for publication in ApJ Letter

Introduction: looking beyond the walls

In its consideration of the remarkable extent and variety of non-university researchers, this book takes a broader view of ‘knowledge’ and ‘research’ than in the many hot debates about today’s knowledge society, ‘learning age’, or organisation of research. It goes beyond the commonly held image of ‘knowledge’ as something produced and owned by the full-time experts to take a look at those engaged in active knowledge building outside the university walls

Brian: The Typographical Error that Brought Early Career Neuroscientists and Artists Together

In the project “Do You Mind?” early career neuroscientists and artists collaborated to produce artworks for exhibition