Function of KAI2 signaling in plant drought adaptation

Drought causes substantial reductions in crop yields worldwide. Therefore, we set out to identify new chemical and genetic factors that regulate drought resistance in Arabidopsis thaliana. Karrikins (KARs) are a class of butenolide compounds found in smoke that promote seed germination, and have been reported to improve seedling vigor under stressful growth conditions. Here, we discovered that mutations in KARRIKIN INSENSITIVE2 (KAI2), encoding the proposed karrikin receptor, result in hypersensitivity to water deprivation. We performed transcriptomic, physiological and biochemical analyses of kai2 plants to understand the basis for KAI2-regulated drought resistance. We found that kai2 mutants have increased rates of water loss and drought-induced cell membrane damage, enlarged stomatal apertures, and higher cuticular permeability. In addition, kai2 plants have reduced anthocyanin biosynthesis during drought, and are hyposensitive to abscisic acid (ABA) in stomatal closure and cotyledon opening assays. We identified genes that are likely associated with the observed physiological and biochemical changes through a genome-wide transcriptome analysis of kai2 under both well-watered and dehydration conditions. These data provide evidence for crosstalk between ABA- and KAI2-dependent signaling pathways in regulating plant responses to drought. A comparison of the strigolactone receptor mutant d14 (DWARF14) to kai2 indicated that strigolactones also contributes to plant drought adaptation, although not by affecting cuticle development. Our findings suggest that chemical or genetic manipulation of KAI2 and D14 signaling may provide novel ways to improve drought resistance

Evolution of X-ray and FUV Disk-Dispersing Radiation Fields

We present new X-ray and Far Ultraviolet (FUV) observations of T Tauri stars covering the age range 1 to 10 Myr. Our goals are to observationally constrain the intensity of radiation fields responsible for evaporating gas from the circumstellar disk and to assess the feasibility of current photoevaporation models, focusing on X-ray and UV radiation. We greatly increase the number of 7-10 Myr old T Tauri stars observed in the X-rays by including observations of the well populated 25 Ori aggregate in the Orion OB1a subassociation. With these new 7-10 Myr objects, we confirm that X-ray emission remains constant from 1-10 Myr. We also show, for the first time, observational evidence for the evolution of FUV radiation fields with a sample of 56 accreting and non-accreting young stars spanning 1 Myr to 1 Gyr. We find that the FUV emission decreases on timescales consistent with the decline of accretion in classical T Tauri stars until reaching the chromospheric level in weak T Tauri stars and debris disks. Overall, we find that the observed strength of high energy radiation is consistent with that required by photoevaporation models to dissipate the disks in timescales of approximately 10 Myr. Finally, we find that the high energy fields that affect gas evolution are not similarly affecting dust evolution; in particular, we find that disks with inner clearings, the transitional disks, have similar levels of FUV emission as full disks.Comment: 41 pages, 12 figure

Cortical Resonance Frequencies Emerge from Network Size and Connectivity

Neural oscillations occur within a wide frequency range with different brain regions exhibiting resonance-like characteristics at specific points in the spectrum. At the microscopic scale, single neurons possess intrinsic oscillatory properties, such that is not yet known whether cortical resonance is consequential to neural oscillations or an emergent property of the networks that interconnect them. Using a network model of loosely-coupled Wilson-Cowan oscillators to simulate a patch of cortical sheet, we demonstrate that the size of the activated network is inversely related to its resonance frequency. Further analysis of the parameter space indicated that the number of excitatory and inhibitory connections, as well as the average transmission delay between units, determined the resonance frequency. The model predicted that if an activated network within the visual cortex increased in size, the resonance frequency of the network would decrease. We tested this prediction experimentally using the steady-state visual evoked potential where we stimulated the visual cortex with different size stimuli at a range of driving frequencies. We demonstrate that the frequency corresponding to peak steady-state response inversely correlated with the size of the network. We conclude that although individual neurons possess resonance properties, oscillatory activity at the macroscopic level is strongly influenced by network interactions, and that the steady-state response can be used to investigate functional networks

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages

Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of LXRα but not LXRβ. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the IL-6 and TNFα promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXRα and LXRβ genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXRα blocked the oxLDL-induced inflammatory response, while knock-down of LXRβ had no effect. We demonstrate a specific and novel role of the LXRα isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation

LXRalpha Regulates oxLDL-Induced Trained Immunity in Macrophages

Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of LXRalpha but not LXRbeta. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the IL-6 and TNFalpha promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXRalpha and LXRbeta genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXRalpha blocked the oxLDL-induced inflammatory response, while knock-down of LXRbeta had no effect. We demonstrate a specific and novel role of the LXRalpha isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

Purpose!#!Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [!##!Methods!#!Using [!##!Results!#!S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%).!##!Conclusions!#!Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41

The karrikin receptor KAI2 promotes drought resistance in <i>Arabidopsis thaliana</i>

<div><p>Drought causes substantial reductions in crop yields worldwide. Therefore, we set out to identify new chemical and genetic factors that regulate drought resistance in <i>Arabidopsis thaliana</i>. Karrikins (KARs) are a class of butenolide compounds found in smoke that promote seed germination, and have been reported to improve seedling vigor under stressful growth conditions. Here, we discovered that mutations in <i>KARRIKIN INSENSITIVE2</i> (<i>KAI2</i>), encoding the proposed karrikin receptor, result in hypersensitivity to water deprivation. We performed transcriptomic, physiological and biochemical analyses of <i>kai2</i> plants to understand the basis for <i>KAI2</i>-regulated drought resistance. We found that <i>kai2</i> mutants have increased rates of water loss and drought-induced cell membrane damage, enlarged stomatal apertures, and higher cuticular permeability. In addition, <i>kai2</i> plants have reduced anthocyanin biosynthesis during drought, and are hyposensitive to abscisic acid (ABA) in stomatal closure and cotyledon opening assays. We identified genes that are likely associated with the observed physiological and biochemical changes through a genome-wide transcriptome analysis of <i>kai2</i> under both well-watered and dehydration conditions. These data provide evidence for crosstalk between ABA- and KAI2-dependent signaling pathways in regulating plant responses to drought. A comparison of the strigolactone receptor mutant <i>d14</i> (<i>DWARF14</i>) to <i>kai2</i> indicated that strigolactones also contributes to plant drought adaptation, although not by affecting cuticle development. Our findings suggest that chemical or genetic manipulation of <i>KAI2</i> and <i>D14</i> signaling may provide novel ways to improve drought resistance.</p></div