The pancreatic and duodenal homeobox 1 (Pdx1) is an essential pancreatic transcription factor. The C-terminal intrinsically disordered domain of Pdx1 (Pdx1-C) has a heavily biased amino acid composition; most notably, 18 of 83 residues are proline, including a hexaproline cluster near the middle of the chain. For these reasons, Pdx1-C is an attractive target for structure characterization, given the availability of suitable methods. To determine the solution ensembles of disordered proteins, we have developed a suite of 13 C direct-detect NMR experiments that provide high spectral quality, even in the presence of strong proline enrichment. Here, we have extended our suite of NMR experiments to include four new pulse programs designed to record backbone residual dipolar couplings in a 13 C, 15 N-CON detection format. Using our NMR strategy, in combination with small-angle X-ray scattering measurements and Monte Carlo simulations, we have determined that Pdx1-C is extended in solution, with a radius of gyration and internal scaling similar to that of an excluded volume polymer, and a subtle tendency toward a collapsed structure to the N-terminal side of the hexaproline sequence. This structure leaves Pdx1-C exposed for interactions with trans-regulatory co-factors that contribute with Pdx1 to transcription control in the cell.
Steady development on photophysical behaviors for a variety of organic fluorophores inspired us to generate anthracene-based fluorescent molecules with a strong acceptor and a significantly weak donor through a π-spacer. Such molecules are found to have substantial twisted conformational orientations in the solid state and enhanced apolar character because of the attachment of tolyl or mesityl group with an anthracenyl core. Upon exposure to a variety of solvents, strong solvatochromism was noticed for 4-nitro compound (84 nm red shift) in contrast to the cyano analogue (18 nm red shift). Both these probes were highly emissive in apolar solvents while nitro-analogue, in particular, could discriminate the solvents of E T (30) (a measure of microscopic solvent polarity) ranging from 31 to 37. Thus, 4-nitro compounds can be successfully employed to detect and differentiate the apolar solvents. On the contrary, the 2-nitro analogue is almost nonemissive for the same range of solvents perhaps because of favorable excited-state intramolecular proton-transfer process. The fundamental understanding of solvatochromic properties through the formation of twisted intramolecular charge-transfer (TICT) state is experimentally analyzed by synthesizing and studying the π-conjugates linked to only benzene in place of nitro or cyanobenzene, which exhibits no solvatochromism and that helped finding the possible emission, originated from the locally excited state. Moreover, the molecular structures for these compounds are determined by the single-crystal X-ray diffraction studies to examine the change in emission properties with molecular packing and alignment in the aggregated state. The measurement of dihedral angles between the substituents and anthracenyl core was helpful in finding the possible extent of electronic conjugations within the system to decipher both solvatochromism and aggregation enhanced emission (AEE)-behavior. The cyano analogue exhibited prominent AEE-behavior, whereas nitro analogues showed the aggregation-caused quenching effect. The reason behind such dissimilarity in solvatochromism and AEE-behavior between cyano- and nitro-linked anthracenyl π-conjugates are also addressed through experimental outcomes.
A facile and efficient protocol has been developed for mild construction of fused pyrimidines via l-proline-catalyzed reaction of 4-hydroxy coumarins, aldehydes, and 2-aminobenzothiazoles/urea. The reaction has been carried out rapidly and efficiently in water under mild and metal-free conditions. Current etiquette has efficiently synthesized the heterocycles and avoids the use of hazardous solvents over conventional organic solvents. A plausible reaction mechanism has been established in this study. This study represents the first case in which l-proline as a homogeneous catalyst has been explored in the synthesis of fused pyrimidines in water in view of simple procedure and acceptable efficiency. This method gives the target product in excellent yield with ease of workup.
Sustainable synthesis of Ni-Al double-layered catalysts by the coprecipitation method is described. Synthesized double-layered catalysts have been characterized by X-ray diffraction, scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared, and thermogravimetric analyses, which confirmed a hydrotalcite-like structure. In addition, the impact of aging time and temperature on the activity of catalyst has been investigated. Furthermore, it has been confirmed by SEM and TEM analyses that the recovered catalyst has retained its structure. It has also been observed that the prepared material has potency to catalyze the reaction without loss in the yield. To explore the reactivity of the material, the catalyst has been examined in the synthesis of N -(2-hydroxyphenyl)benzamide under solvent-free conditions. The overall process afforded the product with high purity and high yields within short time.
The cationic Ru-H complex was found to be an effective catalyst for the dehydrative C-H coupling of phenols with ketones to form the trisubstituted olefin products. The coupling of phenol with linear ketones led to highly stereoselective formation of the ( Z)-olefin products. The dehydrative coupling of phenol with enones and diones efficiently formed the benzopyrene and related oxacyclic derivatives. The reaction of 3,5-dimethoxyphenol with cyclohexanone-2,2,6,6- d 4 showed a significant H/D exchange to both vinyl and α-CH 2 positions on the olefin product (72-75% D). A significant carbon isotope effect was observed on the ortho-arene carbon of the olefin product. The free energies of intermediate species for the entire catalytic cycle were successfully computed by using the DFT method. The DFT study revealed that the E/ Z stereoselectivity is a result of the energy difference in the insertion step of ortho-metalated phenol to an enol form of the ketone substrate (ΔΔ E = 9.6 kcal/mol). The coupling method provides a direct catalytic C-H olefination method for ketones to form trisubstituted olefins without employing any reactive reagents or forming any wasteful byproducts.
Ocean color sensors are crucial for understanding global phytoplankton dynamics. However, the limited life spans of sensors make multisensor data sets necessary for estimating long‐term trends. Discontinuities may be introduced when merging data between sensors, potentially affecting trend estimates and their uncertainties. We use a Bayesian spatiotemporal model to investigate the presence of discontinuities and their impacts on estimated chlorophyll trends. The discontinuities considered are the introduction of Medium Resolution Imaging Spectrometer, Moderate Resolution Imaging Spectroradiometer‐Aqua, and Visible Infrared Imaging Radiometer Suite and the termination of Sea‐Viewing Wide Field‐of‐View Sensor. Discontinuities are detected in ~70% of regions, affecting trend estimates (~60% of regions have statistically different trends) and potentially even biasing trend estimates (opposite sign in ~13% of regions). Considering a single discontinuity increases trend uncertainty by an average of 0.20%/year (0.59%/year for two discontinuities). This difference in trend magnitude and uncertainty highlights the importance of minimizing discontinuities in multisensor records and taking into account discontinuities when analyzing trends.
Urban areas are responsible for a substantial fraction of anthropogenic emissions of greenhouse gases (GHGs) including methane (CH 4 ), with the second largest anthropogenic direct radiative forcing relative to carbon dioxide (CO 2 ). Quantification of urban CH 4 emissions is important for establishing GHG mitigation policies. Comparison of observation‐based and inventory‐based urban CH 4 emissions suggests possible improvements in estimating CH 4 source emissions in urban environments. In this study, we quantify CH 4 emissions from the Baltimore‐Washington area based on the mass balance aircraft flight experiments conducted in Winters 2015 and 2016. The field measurement‐based mean winter CH 4 emission rates from this area were 8.66 ± 4.17 kg/s in 2015 and 9.14 ± 4.49 kg/s in 2016, which are 2.8 times the 2012 average U.S. GHG Inventory‐based emission rate. The observed emission rate is 1.7 times that given in a population‐apportioned state of Maryland inventory. Methane emission rates inferred from carbon monoxide (CO) and CO 2 emission inventories and observed CH 4 /CO and CH 4 /CO 2 enhancement ratios are similar to those from the mass balance approach. The observed ethane‐to‐methane ratios, with a mean value of 3.3% in Winter 2015 and 4.3% in Winter 2016, indicate that the urban natural gas system could be responsible for ~40–60% of total CH 4 emissions from this area. Landfills also appear to be a major contributor, providing 25 ± 15% of the total emissions for the region. Our study suggests there are grounds to reexamine the CH 4 emissions estimates for the Baltimore‐Washington area and to conduct flights in other seasons.
Revenues from hydropower generation often depend on the operator's ability to provide firm power in the presence of uncertain inflows. The primary options available for optimizing revenue are negotiation of a firm power contract before operations begin and adjustment of the reservoir release during operations. Contract and release strategy optimization are closely coupled and most appropriately analyzed with stochastic real‐time control methods. Here we use an ensemble‐based approach to stochastic optimization that provides a convenient way to construct nonparametric revenue probability distributions to explore the implications of uncertainty. The firm power contract is a simplified bilateral fixed price agreement that partially insulates operator and buyer from price fluctuations. The release control laws and firm energy target are jointly optimized to maximize the operator's expected revenue. Revenue probability distributions and related spill performance statistics indicate that predictive operating strategies such as stochastic dynamic programming and model predictive control can give significantly better performance than standard deterministic operating rules. The performance obtained from batch optimization with perfect inflow information establishes a convenient upper bound on potential revenue and provides a baseline for assessing the significance of differences between real‐time operating strategies. Sensitivity analysis indicates that the benefits of predictive operational strategies are greatest for reservoirs with medium nondimensional residence times and less important for reservoirs with large residence times. Overall, probabilistic analysis of the coupled hydropower contract‐operations problem provides a realistic way to assess revenue and risk for reservoirs that must provide firm power when inflows are uncertain.
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and the current pharmacological treatment for DKD is limited to renin-angiotensin system (RAS) inhibitors. Adenosine is detectable in the kidney and is significantly elevated in response to cellular damage. While all 4 known subtypes of adenosine receptors, namely, A 1 AR, A 2a AR, A 2b AR, and A 3 AR, are expressed in the kidney, our previous study has demonstrated that a novel, orally active, species-independent, and selective A 3 AR antagonist, LJ-1888, ameliorates unilateral ureteral obstruction-induced tubulointerstitial fibrosis. The present study examined the protective effects of LJ-2698, which has higher affinity and selectivity for A 3 AR than LJ-1888, on DKD. In experiment I, dose-dependent effects of LJ-2698 were examined by orally administering 1.5, 5, or 10 mg/kg for 12 weeks to 8-week-old db/db mice. In experiment II, the effects of LJ-2698 (10 mg/kg) were compared to those of losartan (1.5 mg/kg), which is a standard treatment for patients with DKD. LJ-2698 effectively prevented kidney injuries such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, inflammation, and oxidative stress in diabetic mice as much as losartan. In addition, inhibition of lipid accumulation along with increases in PGC1α, a master regulator of mitochondrial biogenesis, were demonstrated in diabetic mice treated with either LJ-2698 or losartan. These results suggest that LJ-2698, a selective A 3 AR antagonist, may become a novel therapeutic agent against DKD.