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关键词： inborn errors of immunity   precision medicine   JAK-STAT signaling   cytokine signaling   JAK1   JAK inhibitors   monoallelic expression   mosaicis  

摘要： Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S7031) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S7031 JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1 Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

关键词： Habitat-correlated   Medicinal plant   Protected area   Osmotic tolerance   Salinity tolerance  

摘要： Milk thistle (Silybum marianum) is a valuable medicinal plant and is spread in different habitats over several areas in Iran. However, no information exists about seed germination and its tolerance to osmotic and salinity stresses of Iranian populations. Therefore, seed germination and seedling responses to osmotic and salinity stresses were determined in six Milk thistle populations originated from different native habitats. The populations were collected from six protected areas in Iran. Hence, two laboratory experiments were arranged separately as a completely randomized factorial design to investigate the effect of osmotic and salinity stresses. In the 1 st and 2nd experiment, seeds of six Milk thistle populations were subjected to five osmotic stress levels (0, -0.3, -0.6, -0.9, and -1.2 MPa) and five salinity stress levels (0, 3, 6, 9, and 12 dSm(-1)), respectively. Ghamsar-Barzak ecotype which, has been harvested from a dry climate with the lowest mean annual precipitation and Golestan National Park ecotype which has been harvested from a Mediterranean climate with the highest mean annual precipitation among the protected areas had the highest and lowest tolerance to osmotic, respectively. Generally, biochemical traits including MDA, Proline, DPPH-Scavenging (%), Soluble carbohydrate, and Total phenol were improved by increasing in osmotic severity in all ecotypes. The response to salinity was higher than osmotic in all ecotypes. However, Ghamsar-Barzak ecotype showed more salinity tolerance compared to other ecotypes. Under salinity conditions, MDA, proline, DPPH-Scavenging (%), soluble carbohydrate, and total phenol increased more compared to the control treatment. The highest tolerance to salinity and osmotic stresses was observed in Ghamsar-Barzak ecotype that obtained its seed was from a dry climate with the lowest mean annual precipitation and soil pH and EC are high. Hence, the results of this study demonstrated that habitat-correlated variation in Mil

关键词： Oxazol-5-(4H)-one dye   Solvatochromic properties   Ground and excited state dipole moments   Biochemical properties   Quantum chemical calculations  

摘要： The synthesized 4-(4-formylbenzylidene)-2-phenyloxazol-5(4H)-one was characterized by NMR and IR spectroscopy. The steady-state and time resolved measurements were applied to investigate its solvatochromism, determine dipole moments and elucidate its biological activity. Photophysical properties of the dye were studied in solvents of different polarities. Solute-solvent interactions were analyzed by means of multi-linear regression method using Catalan parameters whereas linear solvent correlation techniques like Lippert-Mataga, McRae and Bakhshiev polarity functions were used to evaluate the singlet excited state dipole moment. The achieved results indicate that the electronic absorption and fluorescence spectra of the oxazolone dye exhibit positive solvatochromism. Moreover, solvent polarizability is the major factor responsible for the observed red shift, thus the non-specific interactions mainly control the photophysical properties of the dye while the contribution of the specific interactions is weaker and mainly depend on solvent acidity. The rise in dipole moment of the dye occurs upon excitation due to the pi-electron density redistribution. The spectroscopic measurements were supported by computational calculations including geometry optimization, spectral and physicochemical properties. The studies were also extended to evaluate bioactivity of the dye. The interaction between oxazolone dye and Concanavalin A was investigated by the fluorescence anisotropy method. The ion transporter action, especially sodium-potassium pump function, and water transport in epithelial tissue were elucidated by the estimation of skin resistance. (C) 2020 Elsevier B.V. All rights reserved.

关键词： Candida tropicalis   Growth curve modelling   Long chain dicarboxylic acids   Oleate esters   Oleyl alcohol   Toxicity tests  

摘要： Despite considerable foaming problems, oleic acid is still the most commonly used substrate for the biochemical production of 9-octadecenedioic acid (DCA). In this paper, the suitability of alternative substrates such as oleyl alcohol, methyl-, ethyl- and butyl oleate, was investigated. First, the toxicity of the alternative substrates to the fermenting yeast C. tropicalis ATCC20962 was determined for different substrate concentrations. It was found that the addition of up to 100 g L-1 of the ester and alcohol substrates showed no growth influence. Since alcohols are expected side products when using ester substrates, the toxicity of the corresponding released alcohols was also evaluated. Methanol and ethanol showed no effect on the growth up to 36 g L-1 and 55 gL(-1) respectively, whereas a half maximum inhibitory concentration (IC50) of 1.4 g L-1 for butanol was found. Using 20 g L-1 oleic acid, oleyl alcohol, methyl oleate and butyl oleate as substrate showed a yield of 14 g L-1, 7 g L-1, 5 gL(-1) and 0.9 g L-1 9-octadecenedioic acid respectively. A qualitative study showed that all four substrates were converted to 9-octadecenedioic acid. Oleic acid resulted in the highest yield whereas oleyl alcohol is the closest candidate for alternative DCA production.

关键词： Cathepsin S   Nitriles   Reversible inhibition   Sulfonamides  

摘要： A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (K-i = 4.02 nM;selectivity ratio cathepsin S/K = 5.8;S/L = 67) and 24 with a 4'-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (K-i = 35.5 nM;selectivity ratio cathepsin S/K = 57;S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.

关键词： Enzymatic hydrolysis   Platform sugar   Cellulose nanocrystals   Nanocellulose  

摘要： This work evaluated the viability of integrating the isolation of cellulose nanocrystals (CNCs) via enzymatic hydrolysis at a high solid loading into the biochemical platform process for the production of sugars from sugarcane bagasse (SCB). SCB was first processed at a biochemical conversion pilot plant and bleached to yield a cellulose-rich pulp, which was enzymatically hydrolyzed at high solid and low enzyme loadings. The resulting hydrolysate had high sugar concentration (> 120 g/L glucose) and the CNCs (20 nm in diameter) isolated directly from the hydrolysis residue showed superior properties (higher thermal stability, higher crystallinity index, and higher particle diameter uniformity) than the CNCs prepared from commercial bleached eucalyptus Kraft pulp. These findings demonstrate the technical viability of the proposed integrated process that combined with the high CNCs yield (approximately50%) and the no need for the costly ultrasonic dispersion treatment step to obtain nanoparticles can further contribute for improving the economic and environmental viability of the proposed enzyme-mediated isolation process.

关键词： Carbon concentrating mechanism   Enzyme activity   Pyropia yezoensis   Photosynthetic efficiency   Transcriptome  

摘要： Background Pyropia yezoensis(Rhodophyta) is widely cultivated in East Asia and plays important economic, ecological and research roles. Although inorganic carbon utilization ofP. yezoensishas been investigated from a physiological aspect, the carbon concentration mechanism (CCM) ofP. yezoensisremains unclear. To explore the CCM ofP. yezoensis, especially during its different life stages, we tracked changes in the transcriptome, photosynthetic efficiency and in key enzyme activities under different inorganic carbon concentrations. Results Photosynthetic efficiency demonstrated that sporophytes were more sensitive to low carbon (LC) than gametophytes, with increased photosynthesis rate during both life stages under high carbon (HC) compared to normal carbon (NC) conditions. The amount of starch and number of plastoglobuli in cells corresponded with the growth reaction to different inorganic carbon (Ci) concentrations. We constructed 18 cDNA libraries from 18 samples (three biological replicates per Ci treatment at two life cycles stages) and sequenced these using the Illumina platform. De novo assembly generated 182,564 unigenes, including approximately 275 unigenes related to CCM. Most genes encoding internal carbonic anhydrase (CA) and bicarbonate transporters involved in the biophysical CCM pathway were induced under LC in comparison with NC, with transcript abundance of somePyCAs in gametophytes typically higher than that in sporophytes. We identified all key genes participating in the C4 pathway and showed that their RNA abundances changed with varying Ci conditions. High decarboxylating activity of PEPCKase and low PEPCase activity were observed inP. yezoensis. Activities of other key enzymes involved in the C4-like pathway were higher under HC than under the other two conditions. Pyruvate carboxylase (PYC) showed higher carboxylation activity than PEPC under these Ci conditions. Isocitrate lyase (ICL) showed high activity, but the activity of malate synthase (M

关键词： Largemouth bass fillets   Ethyl lauroyl arginate hydrochloride   Quality   Biochemical changes   Microbial composition   Chilled storage  

摘要： This study aimed to investigate preservative effects of ethyl lauroyl arginate hydrochloride (LAE) on microbiota, quality, and physiochemical changes of container-cultured largemouth bass fillets stored at 4 degrees C. The results showed LAE treatment was effective in reducing bacterial growth and attenuating physiochemical changes (flesh color, trichloroacetic acid (TCA)-soluble peptides, total volatile basic nitrogen (TVB-N), ammonia concentration, and biogenic amines) of bass fillets, while had relatively weak effect on the degradation of ATP-related compounds. As a result, LAE treatment retarded the deterioration of sensory attributes, and thus prolonged the shelf-life of largemouth bass fillets for 4 days. In addition, LAE treatment decreased the relative abundance of Pseudomonas in bass fillets, and thus changed the microbial composition. Moreover, correlation analysis between physiochemical changes and bacterial genera showed that Pseudomonas was well correlated with TCA-soluble peptides, TVB-N, ammonia, putrescine and histamine, while Aeromonas tended to have strong potentials in producing ammonia and cadaverine.