Targeting of diacylglycerol degradation to M1 muscarinic receptors by beta-arrestins

Seven-transmembrane receptor (7TMR) signaling is transduced by second messengers such as diacylglycerol (DAG) generated in response to the heterotrimeric guanine nucleotide-binding protein Gq and is terminated by receptor desensitization and degradation of the second messengers. We show that beta-arrestins coordinate both processes for the Gq-coupled M1 muscarinic receptor. beta-Arrestins physically interact with diacylglycerol kinases (DGKs), enzymes that degrade DAG. Moreover, beta-arrestins are essential for conversion of DAG to phosphatidic acid after agonist stimulation, and this activity requires recruitment of the beta-arrestin-DGK complex to activated 7TMRs. The dual function of beta-arrestins, limiting production of diacylglycerol (by receptor desensitization) while enhancing its rate of degradation, is analogous to their ability to recruit adenosine 3',5'-monophosphate phosphodiesterases to Gs-coupled beta2-adrenergic receptors. Thus, beta-arrestins can serve similar regulatory functions for disparate classes of 7TMRs through structurally dissimilar enzymes that degrade chemically distinct second messengers.     

Structure of a thiol monolayer-protected gold nanoparticle at 1.1 A resolution

Structural information on nanometer-sized gold particles has been limited, due in part to the problem of preparing homogeneous material. Here we report the crystallization and x-ray structure determination of a p-mercaptobenzoic acid (p-MBA)-protected gold nanoparticle, which comprises 102 gold atoms and 44 p-MBAs. The central gold atoms are packed in a Marks decahedron, surrounded by additional layers of gold atoms in unanticipated geometries. The p-MBAs interact not only with the gold but also with one another, forming a rigid surface layer. The particles are chiral, with the two enantiomers alternating in the crystal lattice. The discrete nature of the particle may be explained by the closing of a 58-electron shell.     

Direct measurement of the reaction front in chemically amplified photoresists

The continuing drive by the semiconductor industry to fabricate smaller structures using photolithography will soon require dimensional control at length scales comparable to the size of the polymeric molecules in the materials used to pattern them. The current technology, chemically amplified photoresists, uses a complex reaction-diffusion process to delineate patterned areas with high spatial resolution. However, nanometer-level control of this critical process is limited by the lack of direct measurements of the reaction front. We demonstrate the use of x-ray and neutron reflectometry as a general method to measure the spatial evolution of the reaction-diffusion process with nanometer resolution. Measuring compositional profiles, provided by deuterium-labeled reactant groups for neutron scattering contrast, we show that the reaction front within the material is broad rather than sharply defined and the compositional profile is altered during development. Measuring the density profile, we directly correlate the developed film structure with that of the reaction front.     

Large magnetic anisotropy of a single atomic spin embedded in a surface molecular network

Magnetic anisotropy allows magnets to maintain their direction of magnetization over time. Using a scanning tunneling microscope to observe spin excitations, we determined the orientation and strength of the anisotropies of individual iron and manganese atoms on a thin layer of copper nitride. The relative intensities of the inelastic tunneling processes are consistent with dipolar interactions, as seen for inelastic neutron scattering. First-principles calculations indicate that the magnetic atoms become incorporated into a polar covalent surface molecular network in the copper nitride. These structures, which provide atom-by-atom accessibility via local probes, have the potential for engineering anisotropies large enough to produce stable magnetization at low temperatures for a single atomic spin.     

TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.     

Impact of anthropogenic CO2 on the CaCO3 system in the oceans

Rising atmospheric carbon dioxide (CO2) concentrations over the past two centuries have led to greater CO2 uptake by the oceans. This acidification process has changed the saturation state of the oceans with respect to calcium carbonate (CaCO3) particles. Here we estimate the in situ CaCO3 dissolution rates for the global oceans from total alkalinity and chlorofluorocarbon data, and we also discuss the future impacts of anthropogenic CO2 on CaCO3 shell-forming species. CaCO3 dissolution rates, ranging from 0.003 to 1.2 micromoles per kilogram per year, are observed beginning near the aragonite saturation horizon. The total water column CaCO3 dissolution rate for the global oceans is approximately 0.5 +/- 0.2 petagrams of CaCO3-C per year, which is approximately 45 to 65% of the export production of CaCO3.     

Isotopic evidence for massive oxidation of organic matter following the great oxidation event

The stable isotope record of marine carbon indicates that the Proterozoic Eon began and ended with extreme fluctuations in the carbon cycle. In both the Paleoproterozoic [2500 to 1600 million years ago (Ma)] and Neoproterozoic (1000 to 542 Ma), extended intervals of anomalously high carbon isotope ratios (δ(13)C) indicate high rates of organic matter burial and release of oxygen to the atmosphere; in the Neoproterozoic, the high δ(13)C interval was punctuated by abrupt swings to low δ(13)C, indicating massive oxidation of organic matter. We report a Paleoproterozoic negative δ(13)C excursion that is similar in magnitude and apparent duration to the Neoproterozoic anomaly. This Shunga-Francevillian anomaly may reflect intense oxidative weathering of rocks as the result of the initial establishment of an oxygen-rich atmosphere.     

Origin and evolution of prebiotic organic matter as inferred from the Tagish Lake meteorite

The complex suite of organic materials in carbonaceous chondrite meteorites probably originally formed in the interstellar medium and/or the solar protoplanetary disk, but was subsequently modified in the meteorites' asteroidal parent bodies. The mechanisms of formation and modification are still very poorly understood. We carried out a systematic study of variations in the mineralogy, petrology, and soluble and insoluble organic matter in distinct fragments of the Tagish Lake meteorite. The variations correlate with indicators of parent body aqueous alteration. At least some molecules of prebiotic importance formed during the alteration.     

Needles in haystacks: Estimating detection probability and occupancy of rare and cryptic snakes

The species most in need of conservation or management are often also the most difficult to monitor, because of their rarity, secretive habits, or both. To combat these challenges, presence/absence (site occupancy) models can be used to track species occupancy at landscape scales. However, quantitative knowledge of detection probability (which is almost always <1) is required to reliably estimate site occupancy. Here, we present a case study that combines detection probabilities and site occupancy modeling to monitor a notoriously secretive guild of animals, North American aquatic snakes. Specifically, we use program PRESENCE to estimate detection probability (p) and probability of site occupancy (ψ) for seven snake species in relationship to site covariates, to understand the proximate and ultimate factors that influence habitat suitability. We were able to estimate p (3–46%) and ψ (12–96%) for each species and calculate the amount of unsuccessful effort necessary to declare absence of each species with statistical confidence (5–63 visits; 150–1890 trap-nights). We documented considerable interspecific variation in p and ψ; one species (Nerodia fasciata) was widespread and highly detectable, while another (Agkistrodon piscivorus) had low detectability despite its wide distribution. Five other species were secretive, or restricted to specific habitat types, or both, illustrating that complex and sometimes counterintuitive relationships exist between capture rate and occupancy. Incorporating p and ψ is essential to the success of large-scale monitoring programs for elusive species.     

Measurement of corneal sensitivity in 20 ophthalmologically normal alpacas

Objective To determine corneal sensitivity in 20 healthy adult alpacas (40 eyes) in order to establish reference values. Design Prospective study. Animals Twenty healthy, adult alpacas. Procedures Corneal sensitivity was determined by the corneal touch threshold (CTT) using a Cochet‐Bonnet esthesiometer. Five different regions of the cornea were evaluated (nasal, ventral, lateral, dorsal, and central). Results Corneal touch threshold values (in mm filament length) obtained from five corneal regions demonstrated varying corneal sensitivities. The central region (34.5 ± 7.1 mm) was the most sensitive, followed by the ventral (29.5 ± 7.2 mm), medial (29.3 ± 7.3 mm), dorsal (25.6 ± 6.3 mm), and lateral (21.8 ± 5.7 mm) regions. All pairwise comparisons of regional differences were statistically significant (P < 0.05), except for the comparison between the ventral and medial regions (P = 0.88). Evaluation of the CCT while controlling for age (2–5 years vs. 6–10 years) demonstrated an increased CTT with an increasing age for the central, ventral, medial and lateral regions. A decrease in the CTT of the dorsal region was noted with increasing age. Conclusion and Clinical Relevance Corneal touch threshold values in 40 eyes of 20 healthy adult alpacas were determined using a Cochet‐Bonnet esthesiometer. This study demonstrated the central corneal region to be most sensitive. Values obtained may serve as reference values in subsequent studies.