Local‐Regional Similarity in Drylands Increases During Multiyear Wet and Dry Periods and in Response to Extreme Events

Climate change is predicted to impact ecosystems through altered precipitation (PPT) regimes. In the Chihuahuan Desert, multiyear wet and dry periods and extreme PPT pulses are the most influential climatic events for vegetation. Vegetation responses are most frequently studied locally, and regional responses are often unclear. We present an approach to quantify correlation of PPT and vegetation responses (as Normalized Difference Vegetation Index [NDVI]) at the Jornada ARS‐LTER site (JRN; 550 km2 area) and the surrounding dryland region (from 0 to 500 km distance; 400,000 km2 study area) as a way to understand regional similarity to locally observed patterns. We focused on fluctuating wet and dry years, multiyear wet or dry periods of 3–4 yr, and multiyear wet periods that contained one or more extreme high PPT pulses or extreme low rainfall. In all but extreme high PPT years, JRN PPT was highly correlated... (See article for full abstract)

Observation of three-photon Greenberger-Horne-Zeilinger entanglement

We present the experimental observation of polarization entanglement for three spatially separated photons. Such states of more than two entangled particles, known as GHZ states, play a crucial role in fundamental tests of quantum mechanics versus local realism and in many quantum information and quantum computation schemes. Our experimental arrangement is such that we start with two pairs of entangled photons and register one photon in a way that any information as to which pair it belongs to is erased. The registered events at the detectors for the remaining three photons then exhibit the desired GHZ correlations.Comment: Revtex, 4 pages, uses floats, epsfi

Signaling from β1- and β2-adrenergic receptors is defined by differential interactions with PDE4

β1- and β2-adrenergic receptors (βARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by β1AR but not β2AR signaling, and chronic stimulation of the two receptors has opposing effects on myocyte apoptosis and cell survival. Differences in the assembly of macromolecular signaling complexes may explain the distinct biological outcomes. Here, we demonstrate that β1AR forms a signaling complex with a cAMP-specific phosphodiesterase (PDE) in a manner inherently different from a β2AR/β-arrestin/PDE complex reported previously. The β1AR binds a PDE variant, PDE4D8, in a direct manner, and occupancy of the receptor by an agonist causes dissociation of this complex. Conversely, agonist binding to the β2AR is a prerequisite for the recruitment of a complex consisting of β-arrestin and the PDE4D variant, PDE4D5, to the receptor. We propose that the distinct modes of interaction with PDEs result in divergent cAMP signals in the vicinity of the two receptors, thus, providing an additional layer of complexity to enforce the specificity of β1- and β2-adrenoceptor signaling

Effects of Physiologic, Metabolic and Molecular Adaptations to Calorie Restriction on Biomarkers of Longevity

Calorie restriction (CR), reducing caloric intake without malnutrition, increases lifespan and delays the onset of age-related diseases. Characterizing the underlying mechanisms that mediate the effects of calorie restriction on aging and lifespan will provide insight into the fundamental biology of aging, as well as guide research into the development of therapeutics for age-related diseases. It seems likely that some combination of physiologic, metabolic and molecular adaptations to CR lead to cellular responses that in-turn increase the longevity of the organism. Thus the goal of this thesis work was to combine a kinetic biomarker strategy with classic physiologic and molecular techniques to determine the role of physiologic adaptations, fat metabolism and molecular signaling on biomarkers of CR-induced longevity in mice. The data presented here demonstrate that CR leads to significant reductions in cell proliferation rates in keratinocytes, liver cells, mammary epithelial cells and splenic T-cells. These reductions in cell proliferation rates cannot be accounted for by reductions in food intake, energy expenditure, fat mass or body weight. In addition, the CR-induced reduction in cell proliferation is not dependent on Sirt1 expression, nor can it be mimicked by resveratrol treatment. However, reductions in cell proliferation rates were associated with a CR-induced increase in whole body fatty acid oxidation and have a strong negative correlation with circulating IGF-1 levels. Taken together these results suggest that increased reliance on fatty acid oxidation and reductions in IGF-1 signaling may be metabolic pathways that mediate the effects of CR on aging and longevity. These results also point to molecular mediators that can translate changes in substrate utilization to regulation of growth factor signaling as potential regulatory nodes necessary for the CR-induced effects on cell proliferation and longevity

Calorie restriction does not increase short-term or long-term protein synthesis

Increased protein synthesis is proposed as a mechanism of life-span extension during caloric restriction (CR). We hypothesized that CR does not increase protein synthesis in all tissues and protein fractions and that any increased protein synthesis with CR would be due to an increased anabolic effect of feeding. We used short- (4 hours) and long-term (6 weeks) methods to measure in vivo protein synthesis in lifelong ad libitum (AL) and CR mice. We did not detect an acute effect of feeding on protein synthesis while liver mitochondrial protein synthesis was lower in CR mice versus AL mice. Mammalian target of rapamycin (mTOR) signaling was repressed in liver and heart from CR mice indicative of energetic stress and suppression of growth. Our main findings were that CR did not increase rates of mixed protein synthesis over the long term or in response to acute feeding, and protein synthesis was maintained despite decreased mTOR signaling

Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates

Calorie restriction (CR) increases longevity and retards the development of many chronic diseases, but the underlying metabolic signals are poorly understood. Increased fatty acid (FA) oxidation and reduced FA synthesis have been hypothesized to be important metabolic adaptations to CR. However, at metabolic steady state, FA oxidation must match FA intake plus synthesis; moreover, FA intake is low, not high, during CR. Therefore, it is not clear how FA dynamics are altered during CR. Accordingly, we measured food intake patterns, whole body fuel selection, endogenous FA synthesis, and gene expression in mice on CR. Within 2 days of CR being started, a shift to a cyclic, diurnal pattern of whole body FA metabolism occurred, with an initial phase of elevated endogenous FA synthesis [respiratory exchange ratio (RER) >1.10, lasting 4-6 h after food provision], followed by a prolonged phase of FA oxidation (RER = 0.70, lasting 18-20 h). CR mice oxidized four times as much fat per day as ad libitum (AL)-fed controls (367 +/- 19 vs. 97 +/- 14 mg/day, P < 0.001) despite reduced energy intake from fat. This increase in FA oxidation was balanced by a threefold increase in adipose tissue FA synthesis compared with AL. Expression of FA synthase and acetyl-CoA carboxylase mRNA were increased in adipose and liver in a time-dependent manner. We conclude that CR induces a surprising metabolic pattern characterized by periods of elevated FA synthesis alternating with periods of FA oxidation disproportionate to dietary FA intake. This pattern may have implications for oxidative damage and disease risk

Fibroblast Growth Factor 21 Is Not Required for the Reductions in Circulating Insulin-Like Growth Factor-1 or Global Cell Proliferation Rates in Response to Moderate Calorie Restriction in Adult Mice

<div><p>Calorie restriction (CR) delays aging and extends lifespan in numerous organisms, including mice. Down-regulation of the somatotropic axis, including a reduction in insulin-like growth factor-1 (IGF-1), likely plays an important role in CR-induced lifespan extension, possibly by reducing cell proliferation rates, thereby delaying replicative senescence and inhibiting tumor promotion. Accordingly, elucidating the mechanism(s) by which IGF-1 is reduced in response to CR holds therapeutic potential in the fight against age-related diseases. Up-regulation of fibroblast growth factor 21 (FGF21) is one possible mechanism given that FGF21 expression is induced in response to nutritional deprivation and has been implicated as a negative regulator of IGF-1 expression. Here we investigated alterations in hepatic growth hormone (GH)-mediated IGF-1 production and signaling as well as the role of FGF21 in the regulation of IGF-1 levels and cell proliferation rates in response to moderate CR in adult mice. We found that in response to moderate CR, circulating GH and hepatic janus kinase 2 (JAK2) phosphorylation levels are unchanged but that hepatic signal transducer and activator of transcription 5 (STAT5) phosphorylation levels are reduced, identifying STAT5 phosphorylation as a potential key site of CR action within the somatotropic axis. Circadian measurements revealed that the relative level of FGF21 expression is both higher and lower in CR vs. ad libitum (AL)-fed mice, depending on the time of measurement. Employing FGF21-knockout mice, we determined that FGF21 is not required for the reduction in IGF-1 levels or cell proliferation rates in response to moderate CR. However, compared to AL-fed WT mice, AL-fed FGF21-knockout mice exhibited higher basal rates of cell proliferation, suggesting anti-mitotic effects of FGF21. This work provides insights into both GH-mediated IGF-1 production in the context of CR and the complex network that regulates FGF21 and IGF-1 expression and cell proliferation rates in response to nutritional status.</p></div

Functional geometry of auditory cortical resting state networks derived from intracranial electrophysiology.

Understanding central auditory processing critically depends on defining underlying auditory cortical networks and their relationship to the rest of the brain. We addressed these questions using resting state functional connectivity derived from human intracranial electroencephalography. Mapping recording sites into a low-dimensional space where proximity represents functional similarity revealed a hierarchical organization. At a fine scale, a group of auditory cortical regions excluded several higher-order auditory areas and segregated maximally from the prefrontal cortex. On mesoscale, the proximity of limbic structures to the auditory cortex suggested a limbic stream that parallels the classically described ventral and dorsal auditory processing streams. Identities of global hubs in anterior temporal and cingulate cortex depended on frequency band, consistent with diverse roles in semantic and cognitive processing. On a macroscale, observed hemispheric asymmetries were not specific for speech and language networks. This approach can be applied to multivariate brain data with respect to development, behavior, and disorders

Circulating and hepatic mRNA levels of IGF-1 and FGF21 in CR mice.

<p>Plasma A) IGF-1 and B) FGF21 levels in AL and CR mice at 2100 h or 2200 h (n = 16–21 per diet). Relative hepatic mRNA expression levels of C) IGF-1 and D) FGF21 in AL and CR mice at 2100 h or 2200 h (n = 29–31 per diet). Hepatic mRNA expression levels were normalized to 18S rRNA and then normalized to the AL group. Student's unpaired two-tailed <i>t</i>-tests were used for all between-group analyses (* p<0.05, ** p<0.0043, *** p<0.0001).</p

Circulating and hepatic mRNA FGF21, IGF-1 and IGFBP-1 levels in WT/AL, WT/CR, FGF21-KO/AL and FGF21-KO/CR mice.

<p>Plasma levels of A) FGF21, C) IGF-1 and E) IGFBP-1 and relative hepatic mRNA expression levels of B) FGF21, D) IGF-1 and F) IGFBP-1 at 1500 h and 1900 h in WT and FGF21-KO mice fed AL or CR (n = 3–12 per genotype per diet per time point). Hepatic mRNA expression levels were normalized to 18S rRNA and then normalized to WT/AL mice at 1500 h. All between-group analyses were performed using a two-way ANOVA with a Bonferroni <i>post hoc</i> test at each time point (* p<0.05, ** p<0.01, *** p<0.001).</p