DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo

Chemogenetic tools such as designer receptors exclusively activated by designer drugs (DREADDs) are routinely used to modulate neuronal and non-neuronal signaling and activity in a relatively noninvasive manner. The first generation of DREADDs were templated from the human muscarinic acetylcholine receptor family and are relatively insensitive to the endogenous agonist acetylcholine but instead are activated by clozapine-N-oxide (CNO). Despite the undisputed success of CNO as an activator of muscarinic DREADDs, it has been known for some time that CNO is subject to a low rate of metabolic conversion to clozapine, raising the need for alternative chemical actuators of muscarinic-based DREADDs. Here we show that DREADD agonist 21 (C21) (11-(1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) is a potent and selective agonist at both excitatory (hM3Dq) and inhibitory (hM4Di) DREADDs and has excellent bioavailability, pharmacokinetic properties, and brain penetrability. We also show that C21-induced activation of hM3Dq and hM4Di in vivo can modulate bidirectional feeding in defined circuits in mice. These results indicate that C21 represents an alternative to CNO for in vivo studies where metabolic conversion of CNO to clozapine is a concern

The impact of low-frequency and rare variants on lipid levels

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes Project imputation in 62,166 samples, we identify association to lipid traits in 93 loci, including 79 previously identified loci with new lead SNPs and 10 new loci, 15 loci with a low-frequency lead SNP and 10 loci with a missense lead SNP, and 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC and APOE) or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2) explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for low-density lipoprotein cholesterol and total cholesterol. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to resequencing

Prompt K_short production in pp collisions at sqrt(s)=0.9 TeV

The production of K_short mesons in pp collisions at a centre-of-mass energy of 0.9 TeV is studied with the LHCb detector at the Large Hadron Collider. The luminosity of the analysed sample is determined using a novel technique, involving measurements of the beam currents, sizes and positions, and is found to be 6.8 +/- 1.0 microbarn^-1. The differential prompt K_short production cross-section is measured as a function of the K_short transverse momentum and rapidity in the region 0 < pT < 1.6 GeV/c and 2.5 < y < 4.0. The data are found to be in reasonable agreement with previous measurements and generator expectations.Comment: 6+18 pages, 6 figures, updated author lis

Groundwater Contamination and Protection Problems in a Small Rural Community

This article addresses the problem of declining water quality in small communities through an examination of the views of a panel of water resource experts. It is based on the premise that sound decision-making may be facilitated when such problems are confronted by experts, rather than individuals or particular interest groups. A detailed report on ground-water contamination by toxic synthetic organic chemicals in Mount Vernon, Iowa was presented to 120 water professionals from the American Mid-West. In spite of incomplete information, the experts strongly supported positive action to limit further pollution of the aquifer. However, the problem was defined as strictly a community issue that warranted minimal financial support from the state or other agencies. There were some differences of opinion between the experts based, in part, on length of ground-water experience, but a general consensus prevailed that policy-making must take local factors into consideration

CCA1 and ELF3 Interact in the Control of Hypocotyl Length and Flowering Time in Arabidopsis1[W][OA]

The circadian clock is an endogenous oscillator with a period of approximately 24 h that allows organisms to anticipate, and respond to, changes in the environment. In Arabidopsis (Arabidopsis thaliana), the circadian clock regulates a wide variety of physiological processes, including hypocotyl elongation and flowering time. CIRCADIAN CLOCK ASSOCIATED1 (CCA1) is a central clock component, and CCA1 overexpression causes circadian dysfunction, elongated hypocotyls, and late flowering. EARLY FLOWERING3 (ELF3) modulates light input to the clock and is also postulated to be part of the clock mechanism. elf3 mutations cause light-dependent arrhythmicity, elongated hypocotyls, and early flowering. Although both genes affect similar processes, their relationship is not clear. Here, we show that CCA1 represses ELF3 by associating with its promoter, completing a CCA1-ELF3 negative feedback loop that places ELF3 within the oscillator. We also show that ELF3 acts downstream of CCA1, mediating the repression of PHYTOCHROME-INTERACTING FACTOR4 (PIF4) and PIF5 in the control of hypocotyl elongation. In the regulation of flowering, our findings show that ELF3 and CCA1 either cooperate or act in parallel through the CONSTANS/FLOWERING LOCUS T pathway. In addition, we show that CCA1 represses GIGANTEA and SUPPRESSOR OF CONSTANS1 by direct interaction with their promoters, revealing additional connections between the circadian clock and the flowering pathways

Measurement of sigma (pp -> bbX) at √s=7 TeV in the forward region

Decays of b hadrons into final states containing a D-0 meson and a muon are used to measure the bb; production cross-section in proton-proton collisions at a centre-of-mass energy of 7 TeV at the LHC. In the pseudorapidity interval 2 < eta < 6 and integrated over all transverse momenta we find that the average cross-section to produce b-flavoured or b-flavoured hadrons is (75.3 +/- 5.4 +/- 13.0) mu b

Resposta do arroz irrigado ao suprimento de amônio e nitrato Rice growth as affected by combined ammonium and nitrate supply

No arroz cultivado sob alagamento, ocorre a elevação dos teores de NH4+ no solo, sendo assim considerada a principal fonte de N para a cultura. Entretanto, o O2 transportado pelo aerênquima e liberado pelas raízes cria um ambiente favorável à nitrificação na rizosfera, determinando a formação de proporções entre amônio e NO3- disponíveis. Nesse caso, acredita-se que o NO3- pode favorecer o desenvolvimento da cultura e ao mesmo tempo evitar a toxidez por NH4+ no solo alagado. Este trabalho foi realizado com o objetivo de avaliar o efeito de diferentes proporções dos íons NH4+ e NO3- no crescimento do arroz em solução nutritiva. O experimento foi realizado em casa de vegetação, no período de setembro a novembro de 2007, em solução nutritiva e substrato inerte, visando criar um meio poroso, para o crescimento radicular com as seguintes proporções de NH4+ e NO3-:100:0, 75:25 e 25:75 % na concentração de 10,0 mmol L-1 de N. Os baldes foram preenchidos com um substrato inerte, visando criar um meio poroso para o desenvolvimento das raízes. Foram comparados os genótipos IRGA 417 (indica) e Sasanishiki (japônica), e avaliadas a produção de biomassa, a distribuição e o comprimento de raízes e a absorção de N, Ca, Mg e K. O NH4+ das proporções 100:0, 75:25 % causou toxidez às plantas, porém, na maior proporção de NO3- , houve redução da toxidez. O suprimento combinado de NH4+ e NO3- aumentou a produção de biomassa em relação ao NH4+ suprido isoladamente. O sistema radicular do arroz cresceu basicamente na camada de 0-10 cm dos cultivares testados, e o maior comprimento ocorreu no tratamento NH4+ 75:25 NO3- para a IRGA 417. O NH4+ afetou negativamente a absorção do Ca, porém não teve efeito sobre a absorção de N, Mg e K. O N, K e Ca total absorvidos indicam maior eficiência de absorção com o suprimento combinado das duas fontes de N no cultivar IRGA 417, porém sem diferença para Sasanishiki. Assim, conclui-se que o NH4+ é tóxico para o arroz em concentrações elevadas. A presença de NO3- é imprescindível para aumentar a absorção de N, melhorando o crescimento e desenvolvimento da planta e a absorção de cátions.<br>In rice cultivated under flooded conditions, the anaerobic condition favors the formation of NH4+ in the soil, and is therefore considered the main available N source for this crop. However, the process of O2 transport through the aerenchyma and its release by roots, create a favorable environment for nitrification in the plant rizosphere. Nitrification intensity determines the proportions between available NH4+ and NO3- . In this case, it is believed that the presence of NO3- can favor rice growth and simultaneously avoid NH4+ toxicity. This experiment was carried out to evaluate the effect of different proportions between NH4+ and NO3- in nutrient solution on rice growth. The experiment was performed in a greenhouse, from September to November 2007, in a nutrient solution with the following NH4+ and NO3- proportions: 100:0, 75:25 and 25:75, in a 10.0 mmol L-1 N concentration. The plots were fulfilled with a inert substrate to create conditions to root growth. The genotypes IRGA 417 and Sasanishiki were compared and the biomass production, root length, root distribution and the N, Ca, Mg and K uptake were evaluated. The presence of NH4+ in the 100:0, 75:25 proportions resulted in plant toxicity, however, as the NO3- proportion increased, toxicity was reduced. The combined supply of NH4+ and NO3- increased biomass production compared to solely NH4+ supply. The rice root system of the two cultivars developed mainly in the 0-10 cm layer and the - greatest root length was observed in the treatment NH4+ 75:25 NO3- for IRGA 417. The presence of NH4+ in soil solution affected negatively calcium absorption, whereas no affect was observed on N, Mg or K absorption. The total absorbed N, K, and Ca indicated a higher absorption efficiency with the combined supply for IRGA 417, but for cultivar Sasanishiki no differences were verified. It was concluded that NH4+ is toxic to rice plants, and is not the main available source of nitrogen. Nitrate is indispensable to increase the N uptake, normal plant growth and total cation absorption