Because O2 and CO2 fluctuations occur in different environments (mountain tops, under the sea, in the ground) at different times (diurnal rhythms, seasonal variation), as well as under different conditions (respiration, photosynthesis), it is remarkable that animals can glean useful information by monitoring external concentrations. The ability to interpret these signals in the context of a variety of other sensory cues is essential to determine whether the appropriate

behavior is attraction, avoidance, or indifference. How animals evaluate O2, CO2, and other environmental cues is an important problem in neural integration and an exciting avenue of investigation. The author thanks Dr. Henk Roelink for generating the figures for this review and Dr. John Ngai for careful reading of the manuscript. This work was in part supported by a grant from the Z-VAD-FMK mw National Institute of Deafness and Communication Disorders 1R01DC006252 (KS). K.S. is an Early Career

Scientist of the Howard Hughes Medical Institute. “
“Effective therapy for Alzheimer’s disease (AD) is a major unmet medical need. The major demographic risk for development of AD is age with risk doubling approximately every 5 years after age 65 such that by the age of 85, one’s chances of having dementia due to AD ranges from 25%–40%. Therefore, the prevalence of AD is expected to double every 20 years, largely because Enzalutamide mouse of an anticipated increase in the average expected life span. Based on estimates that ∼35 million people worldwide have AD today, it is predicted that well over 100 million individuals will have AD in 2050 (Alzheimer’s Association, 2010 and Wimo et al., 2010). If nothing is done, the personal, economic, and societal toll of the ongoing and growing AD epidemic will be immense. Although key aspects of AD pathogenesis remain enigmatic, scientific advances over the

last 25 years have provided sound rationale for the development of potentially disease-modifying AD therapies (Golde, 2005 and Selkoe, 2001). These therapies primarily target the suspected trigger(s) of the disease. Therapies that have advanced the farthest have primarily been developed based on the proposed initiating role of amyloid β-protein (Aβ) aggregates (Golde et al., 2010). These therapeutic advances, coupled Quisqualic acid with advances in early detection of AD-related pathology in nondemented individuals, suggest that concerted translational research efforts focusing on prevention or early intervention could dramatically reduce the incidence and prevalence of AD. However, current trial design involves treatment of symptomatic patients, a setting where failure to show efficacy may be even more likely given the disease progression. Misalignments of the rationale for the therapy, its preclinical testing, and the actual testing of the therapy in human AD clinical trials have resulted in barriers to effective drug development that we must recognize and that will be very challenging to solve.