Advanced graph and sequence neural networks for molecular property prediction and drug discovery.

MOTIVATION: Properties of molecules are indicative of their functions and thus are useful in many applications. With the advances of deep-learning methods, computational approaches for predicting molecular properties are gaining increasing momentum. However, there lacks customized and advanced methods and comprehensive tools for this task currently. RESULTS: Here, we develop a suite of comprehensive machine-learning methods and tools spanning different computational models, molecular representations and loss functions for molecular property prediction and drug discovery. Specifically, we represent molecules as both graphs and sequences. Built on these representations, we develop novel deep models for learning from molecular graphs and sequences. In order to learn effectively from highly imbalanced datasets, we develop advanced loss functions that optimize areas under precision-recall curves (PRCs) and receiver operating characteristic (ROC) curves. Altogether, our work not only serves as a comprehensive tool, but also contributes toward developing novel and advanced graph and sequence-learning methodologies. Results on both online and offline antibiotics discovery and molecular property prediction tasks show that our methods achieve consistent improvements over prior methods. In particular, our methods achieve #1 ranking in terms of both ROC-AUC (area under curve) and PRC-AUC on the AI Cures open challenge for drug discovery related to COVID-19. AVAILABILITY AND IMPLEMENTATION: Our source code is released as part of the MoleculeX library (https://github.com/divelab/MoleculeX) under AdvProp. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Identification and analysis of toxins in novel Bacillus thuringiensis strain Bt S3076-1 against Spodoptera frugiperda and Helicoverpa armigera (Lep.: Noctuidae).

Despite the successful application of toxins from Bacillus thuringiensis as biological control agents against pests, pests are showing resistance against an increasing number of Bacillus thuringiensis toxins due to evolution; thus, new toxins with higher toxicity and broad-spectrum activity against insects are being increasingly identified. To find new toxins, whole genome sequencing of the novel B. thuringiensis strain Bt S3076-1 was performed, and ten predicted toxic genes were identified in this study, including six cry genes, two tpp genes, one cyt gene and one vip gene, among which six were novel toxins. Subsequently, SDS‒PAGE analysis showed that the major proteins at the spore maturation stage were approximately 120 kDa, 70 kDa, 67 kDa, 60 kDa and 40 kDa, while active proteins after trypsin digestion (approximately 70 kDa and 40 kDa) exhibited LC50 values of 149.64 µg/g and 441.47 µg/g against Spodoptera frugiperda and Helicoverpa armigera larvae, respectively. Furthermore, pathological observation results showed that the peritrophic membrane of Spodoptera frugiperda and Helicoverpa armigera larvae was degraded. These findings will provide an experimental reference for further research on the insecticidal activity, toxicity spectrum and synergism of these toxins in Bt S3076-1.

Versatile wheat gluten: functional properties and application in the food-related industry.

Gluten is a key component that allows wheat flour to form a dough, and it is also a byproduct of the production of wheat starch. As a commercial product, wheat gluten is increasingly used in the food-related industry because of its versatile functional properties and wide range of sources. Wheat gluten is manufactured industrially on a large scale through the Martin process and batter process and variants thereof. Gliadin and glutenin impart cohesiveness and elasticity properties, respectively, to wheat gluten. The formation of gluten networks and polymers depends mainly on covalent bonds (disulfide bonds) and noncovalent bonds (ionic bonds, hydrogen bonds, and hydrophobic interactions). The multifunctional properties (viscoelasticity, gelation, foamability, etc.) of wheat gluten are shown by rehydration and other processing techniques. Wheat gluten has been widely used in wheat-based products, food auxiliary agents, food packaging, encapsulation and release of food functional ingredients, food adsorption and heat insulation materials, special purpose foods, and versatile applications. In the future, wheat gluten protein will be used as an important raw material to participate in the development and preparation of various food and degradable materials, and the application potential of wheat gluten in food-related industries will be massive. This review summarizes the main manufacturing processes, composition, and structure of gluten protein, and the various functional properties that support its application in the food and related industries.

The versatile functional properties of wheat gluten are closely related to structureThe application as a binder and substitute for meat is growing in popularityRenewable and degradable gluten-based materials are important exploited fieldsWheat gluten shows vast potential and application value in food-related industry.

Photosynthesis of 3-Alkylated Coumarins from Carboxylic Acids Catalyzed by a Na2S-Based Electron Donor-Acceptor Complex.

A simple and practical electron donor-acceptor (EDA) strategy to synthesize various 3-alkylated coumarins from easily available coumarins and naturally abundant carboxylic acids under photocatalyst-, oxidant-, and additive-free and mild conditions is reported. Using Na2S as the catalytic electron donor, a series of primary, secondary, and tertiary carbon radicals can be efficiently generated, and the EDA complex can be regenerated without an alkaline additive.

Visible-Light-Induced Annulation of Iodonium Ylides and 2-Isocyanobiaryls to Access 6-Arylated Phenanthridines.

A 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4-CzIPN)-photocatalyzed cascade arylation/cyclization reaction of 2-isocyanobiaryls and iodonium ylides was established for the synthesis of 6-arylated phenanthridines. This is the first example of employing iodonium ylides as aryl radical sources in a visible-light-induced radical cascade cyclization reaction.

Paired Electrolysis Enabled Cyanation of Diaryl Diselenides with KSCN Leading to Aryl Selenocyanates.

The first example of paired electrolysis-enabled cyanation of diaryl diselenides, with KSCN as the green cyanating agent, has been developed. A broad range of aryl selenocyanates can be efficiently synthesized under chemical-oxidant- and additive-free, energy-saving and mild conditions.

Electrocatalytic three-component synthesis of 4-halopyrazoles with sodium halide as the halogen source.

The first example of the electrocatalytic multicomponent synthesis of 4-chloro/bromo/iodopyrazoles from hydrazines, acetylacetones and sodium halides under chemical oxidant- and external electrolyte-free conditions has been developed. Sodium halides played a dual role as a halogenation reagent and a supporting electrolyte. Mechanism studies revealed that the bromination reaction proceeded via an ionic pathway, whereas both chlorination and iodination proceeded via a radical pathway.

TRIM16 overexpression inhibits the metastasis of colorectal cancer through mediating Snail degradation.

Tripartite motif containing 16 (TRIM16) is a member of the tripartite motif protein family and functions as a potential tumor suppressor in several cancers. However, the specific function and clinical significance of TRIM16 in colorectal cancer (CRC) remains unclear. In this study, we observed that low TRIM16 expression was detected frequently in primary colorectal cancer (CRC) tissues and was closely associated with a better prognosis. Functional studies demonstrate that TRIM16 overexpression notably inhibits the metastasis abilities of CRC in vivo and in vitro. Mechanistically, our results demonstrated that TRIM16 directly bound and ubiquitinated Snail family transcriptional repressor 1 (Snail), an important transcriptional factor of the epithelial-mesenchymal transition (EMT) process suppressing the EMT in CRC. Additionally, our data revealed that the inhibition effect of TRIM16 on cancer metastasis was dependent on Snail degradation. Collectively, our study is the first to report that TRIM16 plays a crucial anti-tumor role in CRC tumorigenesis. We also provided novel evidence that TRIM16 might act as a prognostic and therapeutic target to assess and inhibit CRC progression.

Blistering1 Modulates Penicillium expansum Virulence Via Vesicle-mediated Protein Secretion.

The blue mold fungus, Penicillium expansum, is a postharvest apple pathogen that contributes to food waste by rotting fruit and by producing harmful mycotoxins (e.g. patulin). To identify genes controlling pathogen virulence, a random T-DNA insertional library was created from wild-type P. expansum strain R19. One transformant, T625, had reduced virulence in apples, blistered mycelial hyphae, and a T-DNA insertion that abolished transcription of the single copy locus in which it was inserted. The gene, Blistering1, encodes a protein with a DnaJ domain, but otherwise has little homology outside the Aspergillaceae, a family of fungi known for producing antibiotics, mycotoxins, and cheese. Because protein secretion is critical for these processes and for host infection, mass spectrometry was used to monitor proteins secreted into liquid media during fungal growth. T625 failed to secrete a set of enzymes that degrade plant cell walls, along with ones that synthesize the three final biosynthetic steps of patulin. Consequently, the culture broth of T625 had significantly reduced capacity to degrade apple tissue and contained 30 times less patulin. Quantitative mass spectrometry of 3,282 mycelial proteins revealed that T625 had altered cellular networks controlling protein processing in the endoplasmic reticulum, protein export, vesicle-mediated transport, and endocytosis. T625 also had reduced proteins controlling mRNA surveillance and RNA processing. Transmission electron microscopy of hyphal cross sections confirmed that T625 formed abnormally enlarged endosomes or vacuoles. These data reveal that Blistering1 affects internal and external protein processing involving vesicle-mediated transport in a family of fungi with medical, commercial, and agricultural importance.

Recent Progress on Synthesis of N,N'-Chelate Organoboron Derivatives.

N,N'-chelate organoboron compounds have been successfully applied in bioimaging, organic light-emitting diodes (OLEDs), functional polymer, photocatalyst, electroluminescent (EL) devices, and other science and technology areas. However, the concise and efficient synthetic methods become more and more significant for material science, biomedical research, or other practical science. Here, we summarized the organoboron-N,N'-chelate derivatives and showed the different routes of their syntheses. Traditional methods to synthesize N,N'-chelate organoboron compounds were mainly using bidentate ligand containing nitrogen reacting with trivalent boron reagents. In this review, we described a series of bidentate ligands, such as bipyridine, 2-(pyridin-2-yl)-1H-indole, 2-(5-methyl-1H-pyrrol-2-yl)quinoline, N-(quinolin-8-yl)acetamide, 1,10-phenanthroline, and diketopyrrolopyrrole (DPP).

Preharvest UVB Application Increases Glucosinolate Contents and Enhances Postharvest Quality of Broccoli Microgreens.

Broccoli microgreens have shown potential health benefits due to their high glucosinolate (GL) levels. Previously, we observed that postharvest UVB treatment did not have much effect on increasing GLs in broccoli microgreens. In this study, we investigated the influence of preharvest UVB irradiation on GL levels in broccoli microgreens. UHPLC-ESI/ITMS analysis showed that preharvest UVB treatments with UVB 0.09 and 0.27 Wh/m2 significantly increased the glucoraphanin (GLR), glucoerucin (GLE), and total aliphatic GL levels by 13.7 and 16.9%, respectively, in broccoli microgreens when measured on harvest day. The nutritional qualities of UVB-treated microgreens were stable during 21-day storage, with only small changes in their GL levels. Broccoli microgreens treated before harvest with UVB 0.27 Wh/m2 and 10 mM CaCl2 spray maintained their overall quality, and had the lowest tissue electrolyte leakage and off-odor values during the storage. Furthermore, preharvest UVB 0.27 Wh/m2 treatment significantly increased GL biosynthesis genes when evaluated before harvest, and reduced the expression level of myrosinase, a gene responsible for GL breakdown during postharvest storage. Overall, preharvest UVB treatment, together with calcium chloride spray, can increase and maintain health-beneficial compound levels such as GLs and prolong the postharvest quality of broccoli microgreens.

Iodine-Catalyzed Synthesis of N,N'-Chelate Organoboron Aminoquinolate.

We disclose a novel method for the synthesis of fluorescent N,N'-chelate organoboron compounds in high efficiency by treatment of aminoquinolates with NaBAr4/R'COOH in the presence of an iodine catalyst. These compounds display high air and thermal stability. A possible catalytic mechanism based on the results of control experiments has been proposed. Fluorescence quantum yield of 3b is up to 0.79 in dichloromethane.

A novel hydroxycinnamoyl transferase for synthesis of hydroxycinnamoyl spermine conjugates in plants.

BACKGROUND: Hydroxycinnamoyl-spermine conjugates (HCSpm) are a class of hydroxycinnamic acid amides (HCAAs), which not only are instrumental in plant development and stress response, but also benefit human health. However, HCSpm are not commonly produced in plants, and the mechanism of their biosynthesis remains unclear. In previous investigations of phenolics in Solanum fruits related to eggplant (Solanum melongena L.), we discovered that Solanum richardii, an African wild relative of eggplant, was rich in HCSpms in fruits. RESULTS: The putative spermine hydroxycinnamoyl transferase (HT) SpmHT was isolated from S. richardii and eggplant. SrSpmHT expression was high in flowers and fruit, and was associated with HCSpm accumulation in S. richardii; however, SpmHT was hardly detected in eggplant cultivars and other wild relatives. Recombinant SpmHT exclusively selected spermine as the acyl acceptor substrate, while showing donor substrate preference in the following order: caffeoyl-CoA, feruloyl-CoA, and p-coumaroyl-CoA. Molecular docking revealed that substrate binding pockets of SpmHT could properly accommodate spermine but not the shorter, more common spermidine. CONCLUSION: SrSpmHT is a novel spermine hydroxycinnamoyl transferase that uses Spm exclusively as the acyl acceptor substrate to produce HCSpms. Our findings shed light on the HCSpm biosynthetic pathway that may allow an increase of health beneficial metabolites in Solanum crops via methods such as introgression or engineering HCAA metabolism.

Continuous amperometric hydrogen gas sensing in ionic liquids.

We report an innovative amperometric hydrogen sensor that addresses current primary issues (i.e. signal drift, low selectivity and speed) in continuous and real-time gas sensing. Utilizing the unique properties and redox reactions of hydrogen in the ionic liquids (ILs), 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide [Bmpy][NTf2] and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [Bmim][NTf2], we demonstrate the real-time and continuous sensing of hydrogen with high sensitivity, selectivity and repeatability in both anaerobic and aerobic conditions using simple constant potential amperometry. The varying adsorption of hydrogen at the IL-electrode interface in different ILs is shown to allow tuning of the sensitivity of the sensor. Taking advantage of oxygen in ambient conditions, we demonstrate that the unique chemical reaction of the analyte with the oxygen enables selective quantification of hydrogen in an ambient environment. A sensor calibration based on a kinetics analysis (i.e. the change of the rate of current signal (ΔI/Δt1/2)) rather than an equilibrium analysis was demonstrated to allow fast and quantitative analysis of hydrogen concentration. The ionic liquid hydrogen sensor exhibits high sensitivity, selectivity, speed, accuracy, repeatability and stability. Together with the miniaturization and affordability of amperometric sensor readout electronics, the IL-based electrochemical gas sensor is expected to enable area-wide sensing instead of point measurements for environmental, health and occupational safety applications.

Calcium Signaling-Mediated Plant Response to Cold Stress.

Low temperatures have adverse impacts on plant growth, developmental processes, crop productivity and food quality. It is becoming clear that Ca2+ signaling plays a crucial role in conferring cold tolerance in plants. However, the role of Ca2+ involved in cold stress response needs to be further elucidated. Recent studies have shown how the perception of cold signals regulate Ca2+ channels to induce Ca2+ transients. In addition, studies have shown how Ca2+ signaling and its cross-talk with nitric oxide (NO), reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPKs) signaling pathways ultimately lead to establishing cold tolerance in plants. Ca2+ signaling also plays a key role through Ca2+/calmodulin-mediated Arabidopsis signal responsive 1 (AtSR1/CAMTA3) when temperatures drop rapidly. This review highlights the current status in Ca2+ signaling-mediated cold tolerance in plants.

Calcium/calmodulin alleviates substrate inhibition in a strawberry UDP-glucosyltransferase involved in fruit anthocyanin biosynthesis.

BACKGROUND: UDP-glucosyltransferase (UGT) is a key enzyme for anthocyanin biosynthesis, which by catalyzing glycosylation of anthocyanidins increases their solubility and accumulation in plants. Previously we showed that pre-harvest spray of CaCl2 enhanced anthocyanin accumulation in strawberry fruit by stimulating the expression of anthocyanin structural genes including a fruit specific FvUGT1. RESULTS: To further understand the regulation of anthocyanin biosynthesis, we conducted kinetic analysis of recombinant FvUGT1 on glycosylation of pelargonidin, the major anthocyanidin in strawberry fruit. At the fixed pelargonidin concentration, FvUGT1 catalyzed the sugar transfer from UDP-glucose basically following Michaelis-Menten kinetics. By contrast, at the fixed UDP-glucose concentration, pelargonidin over 150 µM exhibited marked partial substrate inhibition in an uncompetitive mode. These results suggest that the sugar acceptor at high concentration inhibits FvUGT1 activity by binding to another site in addition to the catalytic site. Furthermore, calcium/calmodulin specifically bound FvUGT1 at a site partially overlapping with the interdomain linker, and significantly relieved the substrate inhibition. In the presence of 0.1 and 0.5 µM calmodulin, V max was increased by 71.4 and 327 %, respectively. CONCLUSIONS: FvUGT1 activity is inhibited by anthocyanidin, the sugar acceptor substrate, and calcium/calmodulin binding to FvUGT1 enhances anthocyanin accumulation via alleviation of this substrate inhibition.

Ca(2+)/calmodulin regulates salicylic-acid-mediated plant immunity.

Intracellular calcium transients during plant-pathogen interactions are necessary early events leading to local and systemic acquired resistance. Salicylic acid, a critical messenger, is also required for both of these responses, but whether and how salicylic acid level is regulated by Ca(2+) signalling during plant-pathogen interaction is unclear. Here we report a mechanism connecting Ca(2+) signal to salicylic-acid-mediated immune response through calmodulin, AtSR1 (also known as CAMTA3), a Ca(2+)/calmodulin-binding transcription factor, and EDS1, an established regulator of salicylic acid level. Constitutive disease resistance and elevated levels of salicylic acid in loss-of-function alleles of Arabidopsis AtSR1 suggest that AtSR1 is a negative regulator of plant immunity. This was confirmed by epistasis analysis with mutants of compromised salicylic acid accumulation and disease resistance. We show that AtSR1 interacts with the promoter of EDS1 and represses its expression. Furthermore, Ca(2+)/calmodulin-binding to AtSR1 is required for suppression of plant defence, indicating a direct role for Ca(2+)/calmodulin in regulating the function of AtSR1. These results reveal a previously unknown regulatory mechanism linking Ca(2+) signalling to salicylic acid level.

Beneficial effect of splanchnic nerve transection and harmful effect of vagotomy on acute necrotizing pancreatitis in the dog.

BACKGROUND: The nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. However, the influence of visceral nerve (VN) on acute necrotizing pancreatitis (ANP) has drawn little attention. AIM: To investigate the influence of VN on the pathophysiological process of ANP in dogs. METHODS: The dogs were divided into a sham operation (SO) group, ANP group, ANP + vagal nerve trunk transection (VNTT) group, and ANP + greater splanchnic nerve transection (GSNT) group. The VNTT and GSNT groups underwent VNTT and GSNT respectively immediately after ANP induction. The levels of serum pancreatic amylase (AMY), calcium, high-sensitivity C-reactive protein (HCRP), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-10 (IL-10) were monitored dynamically and the pathological examinations of the pancreas was performed at postoperative day 7. RESULTS: All serum parameters among the four groups showed no differences before the experiment (p > 0.05). At different postoperative times, the serum TNF-α, IL-1ß, HCRP, and AMY were significantly increased, however, the serum calcium and IL-10 had dropped in the ANP group versus SO group (p < 0.05); an alike variation trend occurred between the VNTT group and ANP group (p < 0.05); an opposite variation trend occurred between the GSNT group and the ANP group (p < 0.05). The pancreas pathological scoring of VNTT group was highest in the four groups (p < 0.05) and GSNT group was lower versus ANP group (p < 0.05). CONCLUSIONS: The GSNT has been shown to alleviate development of ANP, however, VNTT may exacerbate the ANP.

Impact of pulmonary infection after radical esophagectomy on serum inflammatory markers, pulmonary function indices, and prognosis.

OBJECTIVES: To analyze the influence of pulmonary infection after radical esophagectomy on serum inflammatory markers, pulmonary function, and prognosis. METHODS: We enrolled 278 esophageal cancer patients who underwent radical esophagectomy. Patients were split into the infected (n=51) and uninfected groups (n=227). The inflammatory parameters, complications, and prognosis were compared. RESULTS: In the infected group, interleukin (IL)-6 was 16.19±2.63 ng/L, tumor necrosis factor-α was 19.64±3.07 µg/L, and IL-1ß was 22.49±5.13 ng/L at 7 days postoperatively; white blood cell counts was 12.65±2.14 ×109/L, percentage of neutrophils (NEU%) was 67.04±10.48%, and platelet (PLT) counts was 249.82±63.26 ×109/L; the increasing ranges of the above factors after the operation were much raised compared with the uninfected group (p<0.05). Compared with the uninfected group, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC were greater declines in ranges (p<0.05), and the arrhythmia incidence and the mortality within 60 days postoperatively were greater in the infected group (p<0.05). CONCLUSION: Postoperative pulmonary infection can lead to pulmonary function damage, proinflammatory factor overexpression, and an increased risk of early death.

Nutrients and non-essential metals in darkibor kale grown at urban and rural farms: A pilot study.

Kale is a nutrient-dense leafy vegetable associated with wide-ranging health benefits. It is tolerant of drought and temperature fluctuations, and could thus serve an increasingly important role in providing a safe and nutritious food supply during the climate crisis, while kale's ease of cultivation and ability to be grown in a wide range of soils make it a good fit for urban agriculture. In this pilot study we explored potential differences between kale grown at urban versus rural farms. We planted kale seedlings (Darkibor variety) at three urban and four rural farms in and around Baltimore City, Maryland, instructed farmers to cultivate them using their usual growing practices, harvested the kale from fields and points of distribution, and analyzed it for concentrations of carotenoids, vitamins C and K1, ten nutritional elements, and eight non-essential metals. Although sample sizes for some analyses were in some cases too small to produce statistically significant results, we identified potentially meaningful differences in concentrations of several components between urban and rural kale samples. Compared to urban samples, mean concentrations of carotenoids and vitamins were 22-38% higher in rural field samples. By contrast, mean concentrations for eight nutritional elements were higher in urban field samples by as much as 413% for iron. Compared to rural field samples, mean concentrations of nine non-essential metals were higher in urban samples, although lead and cadmium concentrations for all samples were below public health guidelines. Some urban-rural differences were more pronounced than those identified in prior research. For six elements, variance within urban and rural farms was greater than variance between urban and rural farms, suggesting urbanicity may not be the primary driver of some observed differences. For some nutrients, mean concentrations were higher than upper ranges reported in prior estimates, suggesting kale may have the potential to be more nutrient-dense than previously estimated. The nutritive and metals composition of this important crop, and the factors that influence it, merit continued investigation given its growing popularity.