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Microbial natural products form the basis of most of the antibiotics used in the clinic. The vast majority has not yet been discovered, among others because the hidden chemical space is obscured by previously identified (and typically abundant) antibiotics in culture extracts. Efficient dereplication is therefore key to the discovery of our future medicines. Here we present an analytical platform for the efficient identification and prioritization of low abundance bioactive compounds at nanoliter scale, called nanoRAPIDS. NanoRAPIDS encompasses analytical scale separation and nanofractionation of natural extracts, followed by the bioassay of interest, automated mass spectrometry identification, and Global Natural Products Social molecular networking (GNPS) for dereplication. As little as 10 μL crude extract is fractionated into 384 fractions. First, bioactive congeners of iturins and surfactins were identified in Bacillus, based on their bioactivity. Subsequently, bioactive molecules were identified in an extensive network of angucyclines elicited by catechol in cultures of Streptomyces sp. This allowed the discovery of a highly unusual N-acetylcysteine conjugate of saquayamycin, despite low production levels in an otherwise abundant molecular family. These data underline the utility and broad application of the technology for the prioritization of minor bioactive compounds in complex extracts. Microbial natural products are an important source for antibiotic discovery, however, their efficient dereplication remains challenging. Here, the authors develop an analytical pipeline, nanoRAPIDS, to prioritize low abundance bioactive compounds at nanoscale, by integrating the bioassay of interest, automated mass spectrometry identification and GNPS-based dereplication, resulting in the discovery of saquayamycin N from Streptomyces sp. MBT84. [ABSTRACT FROM AUTHOR]

Iso‐maleimycin, a previously unknown constitutional isomer of the antibiotic maleimycin, has been detected in an extract of Streptomyces sp. QL37. Chemical synthesis of both maleimycin (20 % yield over seven steps) and iso‐maleimycin, (15 % yield over six steps) allowed access to reference materials for identification. Gas Chromatography coupled Mass Spectrometry (GC‐MS) analysis demonstrated that of the two isomers, only iso‐maleimycin was present in the extract. This finding supports our hypothesis that iso‐maleimycin is a biosynthetic intermediate of lugdunomycin. Iso‐maleimycin displays low antibiotic activity, with a Minimum Inhibitory Concentration (MIC) value on both E. coli and B. subtilis of 250 µg/mL. [ABSTRACT FROM AUTHOR]

Recent research and policy studies on the low-carbon future highlight the importance of flexible electricity demand. This might be problematic particularly for residential electricity demand, which is related to simultaneous consumers' practices in the household. This paper analyses issues of simultaneity in residential electricity demand in Spain. It makes use of the 2011 Spanish Time Use Survey data with comparisons from the previous Spanish Time Use Survey and the Harmonised European Time Use Surveys. Findings show that media activities are associated with the highest levels of continuity and simultaneity, particularly in the early and late parts of the evening during weekdays. [ABSTRACT FROM AUTHOR]

The starting point of the operation and maintenance tasks in photovoltaic plants is the continuous monitoring and supervision of its components. The great amount of registered data requires a major improvement in the ways this information is processed and analyzed to rapidly detect any potential fault, without incurring additional costs. In this paper, a procedure to perform a detailed graphical supported analysis of the operation of photovoltaic installations, based on inverter data, and using a self-developed application, is presented. The program carries out the automated processing of the registered data, providing their access and visualization by means of color maps. These graphs allow a large volume of data set to be simultaneously represented in a readable way, enabling operation and maintenance operators to quickly detect patterns that would require any type of intervention. As a case study, the operation of a grid-connected photovoltaic plant located in southern Spain was studied during a period of three years. The average daily efficiency values of the PV modules and inverters were in the range of 7.6-14.6%, and 73.5-94% respectively. Moreover, the presence of shadings, as well as the hours and days mainly affected by this issue, was easily detected. [ABSTRACT FROM AUTHOR]

The aim of this investigation was to determine the isoflurane-sparing effect and impact on arterial blood pressure and anaesthetic recovery of a constant rate infusion of medetomidine-propofol in horses. In a prospective, crossover, randomised study, six healthy horses (mean±SD age, 13.7 ±7.7 years; weight, 433 ± 51 kg) were anaesthetised twice with isoflurane and were randomly assigned to receive one of two treatments on each occasion, at least 2 weeks apart. The first treatment was saline (CTL group) and the second a medetomidine-propofol infusion (MP group; 1.25 pg/kg/h medetomidine and 3 mg/kg/h propofol). The isoflurane minimum alveolar concentration (MAC) was determined and the reduction in anaesthetic requirements was calculated. Cardiopulmonary data were recorded at different intervals during the procedure and anaesthetic recovery was blindly assessed using three independent scales. The MAC in the MP group (0.43 ± 0.08%) was 65% lower than in the CTL group (1.23 ± 0.10%). The MP group had a higher mean arterial blood pressure and required less dobutamine than the CTL group. The recovery quality in both groups was considered fair or good and an improvement was observed using the Donaldson scale in the MP group. The administration of a medetomidine-propofol constant rate infusion reduced anaesthetic isoflurane requirements to a clinically significant extent and improved stability of arterial blood pressure together with a good quality recovery. This regime could be useful for providing balanced anaesthesia in horses. [ABSTRACT FROM AUTHOR]

This paper describes a procedure for experimental determination of metastable and resonant populations along a surface wave argon plasma column at atmospheric pressure. As modeling work progresses extensively, an experimental database is necessary to confirm these models. Obtained results, within the range of values reported in literature, indicate that densities of metastable and resonant levels grow along the plasma column for positions near the energy coupler device, where the energy of the surface wave which creates discharge is the highest. This behavior is also found for electron density and temperature; however, it is not the same for gradient. Therefore, at atmospheric pressure, populations of 4s levels are not only controlled by collision with electrons from ground state, but the dissociative recombination mechanism is also important, in agreement with results found by other authors using collisional-radiative models. [ABSTRACT FROM AUTHOR]

Farnesoid X receptor (FXR) activation reduces renal inflammation, but the underlying mechanisms remain elusive. Neutrophil extracellular traps (NETs) are webs of DNA formed when neutrophils undergo specialized programmed cell death (NETosis). The signaling lipid sphingosine-1-phosphate (S1P) stimulates NETosis via its receptor on neutrophils. Here, we identify FXR as a negative regulator of NETosis via repressing S1P signaling. We determined the effects of the FXR agonist obeticholic acid (OCA) in mouse models of adenosine phosphoribosyltransferase (APRT) deficiency and Alport syndrome, both genetic disorders that cause chronic kidney disease. Renal FXR activity is greatly reduced in both models, and FXR agonism reduces disease severity. Renal NETosis and sphingosine kinase 1 (Sphk1) expression are increased in diseased mice, and they are reduced by OCA in both models. Genetic deletion of FXR increases Sphk1 expression, and Sphk1 expression correlates with NETosis. Importantly, kidney S1P levels in Alport mice are two-fold higher than controls, and FXR agonism restores them back to baseline. Short-term inhibition of sphingosine synthesis in Alport mice with severe kidney disease reverses NETosis, establishing a causal relationship between S1P signaling and renal NETosis. Finally, extensive NETosis is present in human Alport kidney biopsies (six male, nine female), and NETosis severity correlates with clinical markers of kidney disease. This suggests the potential clinical relevance of the newly identified FXR-S1P-NETosis pathway. In summary, FXR agonism represses kidney Sphk1 expression. This inhibits renal S1P signaling, thereby reducing neutrophilic inflammation and NETosis. NEW & NOTEWORTHY Many preclinical studies have shown that the farnesoid X receptor (FXR) reduces renal inflammation, but the mechanism is poorly understood. This report identifies FXR as a novel regulator of neutrophilic inflammation and NETosis via the inhibition of sphingosine-1-phosphate signaling. Additionally, NETosis severity in human Alport kidney biopsies correlates with clinical markers of kidney disease. A better understanding of this signaling axis may lead to novel treatments that prevent renal inflammation and chronic kidney disease. [ABSTRACT FROM AUTHOR]

Reduction of CO2 emissions is a main target in the future smart grid. This goal is boosting the installation of renewable energy resources (RES), as well as a major consumer engagement that seeks for a more efficient utilization of these resources toward the figure of 'prosumers'. Nevertheless, these resources present an intermittent nature, which requires the presence of an energy storage system and an energy management system (EMS) to ensure an uninterrupted power supply. Moreover, network-related issues might arise due to the increasing power of renewable resources installed in the grid, the storage systems also being capable of contributing to the network stability. However, to assess these future scenarios and test the control strategies, a simulation system is needed. The aim of this paper is to analyze the interaction between residential consumers with high penetration of PV generation and distributed storage and the grid by means of a high temporal resolution simulation scenario based on a stochastic residential load model and PV production records. Results of the model are presented for different PV power rates and storage capacities, as well as a two-level charging strategy as a mechanism for increasing the hosting capacity (HC) of the network. [ABSTRACT FROM AUTHOR]

R3613 --> 856.4 --> Objective: This study investigates the protective properties of farsenoid X receptor (FXR) agonism by the drug Obeticholic Acid (OCA) in the adenine‐induced tubulointerstitial fibrosis model of kidney disease male and female mice. Hypothesis: OCA treatment will decrease the expression of SMAD3 and phosphorylated‐SMAD3, and therefore will be nephroprotective in the adenine model of kidney disease in male and female mice. Methods: Male and female C57BL/6J mice (12 weeks old) were fed chow (Research Diets D1912040li) or chow admixed with adenine (0.2% w/w) ad lib for 7 weeks. Mice were treated with either vehicle (corn oil) or obeticholic acid (10 mg/kg BW) by gavage 5 days per week. Plasma and organs were collected and processed for bio‐chemical analysis. Results: OCA treatment reduced BUN and plasma creatinine in diseased mice of both sexes. FXR agonism reduced SMAD3 expression in both male (P<0.05) and female (P<0.05) mice. Importantly, FXR agonism also reduced SMAD3 phosphorylation in both male (P<0.05) and female (P<0.001) mice. On histology, OCA reduced renal fibrosis in male (P<0.05) but not female mice. Conclusions: FXR agonism by OCA is anti‐fibrotic in the adenine model of tubulointerstitial fibrotic crystalline nephropathy in male and female mice. Mechanistically, OCA prevents renal fibrosis by reducing SMAD3 expression and phosphorylation. [ABSTRACT FROM AUTHOR]

Actinobacteria are a rich source of bioactive molecules, and genome sequencing has shown that the vast majority of their biosynthetic potential has yet to be explored. However, many of their biosynthetic gene clusters (BGCs) are poorly expressed in the laboratory, which prevents discovery of their cognate natural products. To exploit their full biosynthetic potential, better understanding of the signals that promote the expression of BGCs is needed. Here, we show that the human stress hormone epinephrine (adrenaline) elicits siderophore production by Actinobacteria. Catechol was established as the likely eliciting moiety, since similar responses were seen for catechol and for the catechol-containing molecules dopamine and catechin but not for related molecules. Exploration of the catechol-responsive strain Streptomyces sp. MBT84 using mass spectral networking revealed elicitation of a BGC that produces the angucycline glycosides aquayamycin, urdamycinone B and galtamycin C. Heterologous expression of the catechol-cleaving enzymes catechol 1,2-dioxygenase or catechol 2,3-dioxygenase counteracted the eliciting effect of catechol. Thus, our work identifies the ubiquitous catechol moiety as a novel elicitor of the expression of BGCs for specialized metabolites. The biosynthetic gene clusters of Actinobacteria are poorly expressed in the laboratory, necessitating a better understanding of the signals that promote their expression in order to exploit their full biosynthetic potential. Here, the authors show that the stress hormone epinephrine elicits the expression of biosynthetic gene clusters and influences the metabolism of Streptomyces, with the catechol moiety proving key to this response. [ABSTRACT FROM AUTHOR]

This paper presents a stochastic framework for the optimization of microgrids that has the functionality of providing flexibility services to System Operators (SOs) considering uncertainties in the energy forecast. The methodology is developed with the aim of being applied to complex microgrids composed of different distributed energy resources and hybrid energy storage systems (ESS). The associated optimization problem is operated in two stages: the first one performs a stochastic optimization of the microgrid in order to reserve an up/down regulation capacity with which to deal with the energy forecast uncertainties of the microgrid. The different microgrid devices are optimized by considering their operational costs in order to achieve their optimal operation in the Day-Ahead Market (DM). The second stage is used to re-schedule the initial planning according to the signal request and an economic offer from the SO. The control problem is developed using Stochastic Model Predictive Control (SMPC) techniques and Mixed-Integer Quadratic Programming (MIQP), owing to the presence of logic, integer, mixed and probabilistic variables. The simulation results show that the proposed methodology reduces the risk of undergoing up/down-penalty deviations in the Regulation Service Market (RM), also being able to provide flexibility services to the SOs, despite being subject to uncertainties in the energy forecast carried out for the microgrid. [ABSTRACT FROM AUTHOR]

Over the last 30 years, nuclear receptors (NRs) have been increasingly recognized as key modulators of systemic homeostasis and as contributing factors in many diseases. In the kidney, NRs play numerous important roles in maintaining homeostasis—many of which continue to be unraveled. As "master regulators", these important transcription factors integrate and coordinate many renal processes such as circadian responses, lipid metabolism, fatty acid oxidation, glucose handling, and inflammatory responses. The use of recently-developed genetic tools and small molecule modulators have allowed for detailed studies of how renal NRs contribute to kidney homeostasis. Importantly, while NRs are intimately involved in proper kidney function, they are also implicated in a variety of renal diseases such as diabetes, acute kidney injury, and other conditions such as aging. In the last 10 years, our understanding of renal disease etiology and progression has been greatly shaped by knowledge regarding how NRs are dysregulated in these conditions. Importantly, NRs have also become attractive therapeutic targets for attenuation of renal diseases, and their modulation for this purpose has been the subject of intense investigation. Here, we review the role in health and disease of six key renal NRs including the peroxisome proliferator-activated receptors (PPAR), estrogen-related receptors (ERR), the farnesoid X receptors (FXR), estrogen receptors (ER), liver X receptors (LXR), and vitamin D receptors (VDR) with an emphasis on recent findings over the last decade. These NRs have generated a wealth of data over the last 10 years that demonstrate their crucial role in maintaining normal renal homeostasis as well as their capacity to modulate disease progression. [ABSTRACT FROM AUTHOR]

There is, at present, considerable interest in the storage and dispatchability of photovoltaic (PV) energy, together with the need to manage power flows in real-time. This paper presents a new system, PV-on time, which has been developed to supervise the operating mode of a Grid-Connected Utility-Scale PV Power Plant in order to ensure the reliability and continuity of its supply. This system presents an architecture of acquisition devices, including wireless sensors distributed around the plant, which measure the required information. It is also equipped with a high-precision protocol for synchronizing all data acquisition equipment, something that is necessary for correctly establishing relationships among events in the plant. Moreover, a system for monitoring and supervising all of the distributed devices, as well as for the real-time treatment of all the registered information, is presented. Performances were analyzed in a 400 kW transformation center belonging to a 6.1 MW Utility-Scale PV Power Plant. In addition to monitoring the performance of all of the PV plant's components and detecting any failures or deviations in production, this system enables users to control the power quality of the signal injected and the influence of the installation on the distribution grid. [ABSTRACT FROM AUTHOR]

Objective--To evaluate the duration of effects on movement patterns of horses after sedation with equipotent doses of xylazine hydrochloride, detomidine hydrochloride, or romifidine hydrochloride and determine whether accelerometry can be used to quantify differences among drug treatments. Animals--6 healthy horses. Procedures--Each horse was injected IV with saline (0.9% NaCI) solution (10 mL), xylazine diluted in saline solution (0.5 mg/kg), detomidine diluted in saline solution (0.01 mg/kg), or romifidine diluted in saline solution (0.04 mg/kg) in random order. A triaxial accelerometric device was used for gait assessment 15 minutes before and 5, 15, 30, 45, 60, 75, 90, 105, and 120 minutes after each treatment. Eight variables were calculated, including speed, stride frequency, stride length, regularity, dorsoventral power, propulsive power, mediolateral power, and total power; the force of acceleration and 3 components of power were then calculated. Results--Significant differences were evident in stride frequency and regularity between treatments with saline solution and each α2-adrenoceptor agonist drug; in speed, dorsoventral power, propulsive power, total power, and force values between treatments with saline solution and detomldine or romifidine; and in mediolateral power between treatments with saline solution and detomidine. Stride length did not differ among treatments. Conclusions and Clinical Relevance--Accelerometric evaluation of horses administered α2-adrenoceptor agonist drugs revealed more prolonged sedative effects of romifidine, compared with effects of xylazine or detomidine. Accelerometry could be useful in assessing the effects of other sedatives and analgesics. Accelerometric data may be helpful in drug selection for situations in which a horse's balance and coordination are important. [ABSTRACT FROM AUTHOR]