Sniff-synchronized, gradient-guided olfactory search by freely moving mice.

For many organisms, searching for relevant targets such as food or mates entails active, strategic sampling of the environment. Finding odorous targets may be the most ancient search problem that motile organisms evolved to solve. While chemosensory navigation has been well characterized in microorganisms and invertebrates, spatial olfaction in vertebrates is poorly understood. We have established an olfactory search assay in which freely moving mice navigate noisy concentration gradients of airborne odor. Mice solve this task using concentration gradient cues and do not require stereo olfaction for performance. During task performance, respiration and nose movement are synchronized with tens of milliseconds precision. This synchrony is present during trials and largely absent during inter-trial intervals, suggesting that sniff-synchronized nose movement is a strategic behavioral state rather than simply a constant accompaniment to fast breathing. To reveal the spatiotemporal structure of these active sensing movements, we used machine learning methods to parse motion trajectories into elementary movement motifs. Motifs fall into two clusters, which correspond to investigation and approach states. Investigation motifs lock precisely to sniffing, such that the individual motifs preferentially occur at specific phases of the sniff cycle. The allocentric structure of investigation and approach indicates an advantage to sampling both sides of the sharpest part of the odor gradient, consistent with a serial-sniff strategy for gradient sensing. This work clarifies sensorimotor strategies for mouse olfactory search and guides ongoing work into the underlying neural mechanisms

Writing in Britain and Ireland, c. 400 to c. 800

No abstract available

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Ionic strength dependence of the hysteresis in the polyriboadenylate-polyribouridylate system

Spodheim M, Neumann E. Ionic strength dependence of the hysteresis in the polyriboadenylate-polyribouridylate system. Biophysical Chemistry. 1975;3(2):109-124.The hysteresis observed in cyclic acid-base titrations of the three-stranded polyribonucleotide helix poly (A) 2 poly(U) strongly depends on ionic strength. For NaCl and at 25° C, hysteresis occurs in the limited concentration range between 0.03 M and 1.0 M(NaCl). The transition points, associated with the cyclic conversions between the triple helix and the poly(A) poly(A) double helix and (free) poly(U) constitute a (pH ionic strength) phase diagram covering the ranges of stability and metastability of the hysteresis system. Variations with NaCl concentration of some hysteresis parameters can be quantitatively described in terms of polyelectrolyte theories based on the cylinder-cell model for rodlike polyions. The results of this analysis suggest that the metastability is predominantly due to electrostatic energy barriers preventing the equilibrium transition of the partially protonated triple helix above a critical pH value. Ultraviolet absorbance and potentiometric titration data of poly (A) in the acidic pH range can be analyzed in terms of two types of double-helical structures. Spectrophotometric titrations reveal isosbestic wavelengths for structural transitions of poly (A). Time effects commonly observed in poly (A) titrations are suggested to reflect helix-helix transitions between the two acidic structures

Imaging Glomerular Signaling of Unrestrained Olfactory Search in mice

Project files include 1 page pdf.Olfaction is vital for many crucial animal behaviors such as social interaction, avoiding predators, and locating food. Our goal is to understand how an animal navigates toward the source of an odor. However, little is known about how odors are coded to inform olfactory search behavior. Air turbulence can cause odor distributions to be highly variable and unpredictable. Although we have previously characterized specific behavioral patterns in turbulent odor plumes, little is known about how odors are translated into movements. Our goal is to capture and understand the sensory input that informs these previously observed behaviors. We do this by injecting iGluSnFR, a fluorescent glutamate reporter, into the mitral cell layer of the olfactory bulb. This reporter tells us how glutamate released from olfactory sensory neuron terminals influences activity of mitral cells. iGluSnFR's fast kinetics allows us to observe and measure glutamate levels as the mouse performs olfactory navigation. By revealing activity in olfactory sensory neurons during olfactory navigation, this technique can tell us how odor informs the mouse's brain during active sampling. Following the development of this technique, we will image from iGluSnFR mice performing our olfactory search task to determine the neural computation that connects movement and sensation. Understanding how mice translate odor into behavior will inform our understanding of active sensory sampling behaviors in humans.Alden Schola

Communication between noncontacting macromolecules

We present a quantitative experimental demonstration of solvent-mediated communication between noncontacting biopolymers. We show that changes in the activity of a solvent component brought about by a conformational change in one biopolymer can result in changes in the physical properties of a second noncontacting biopolymer present in solution. Specifically, we show that the release of protons on denaturation of a donor polymer (in this case, a four-stranded DNA tetraplex, iDNA) modulates the melting temperature of a noncontacting, acceptor polymer [in this case poly(A)]. In addition to such proton-mediated cross talk, we also demonstrate counterion-mediated cross talk between noncontacting biopolymers. Specifically, we show that counterion association/release on denaturation of native salmon sperm DNA (the donor polymer) can modulate the melting temperature of poly(dA)⋅poly(dT) (the acceptor polymer). Taken together, these two examples demonstrate how poly(A) and poly(dA)⋅poly(dT) can serve as molecular probes that report the pH and free salt concentrations in solution, respectively. Further, we demonstrate how such through-solvent dialogue between biopolymers that do not directly interact can be used to evaluate (in a model-free manner) association/dissociation reactions of solvent components (e.g., protons, sodium cations) with one of the two biopolymers. We propose that such through-solution dialogue is a general property of all biopolymers. As a result, such solvent-mediated cross talk should be considered when assessing reactions of multicomponent systems such as those that exist in essentially all biological processes