N-monoarylacetothioureas as potent urease inhibitors: synthesis, SAR, and biological evaluation.

A urease inhibitor with good in vivo profile is considered as an alternative agent for treating infections caused by urease-producing bacteria such as Helicobacter pylori. Here, we report a series of N-monosubstituted thioureas, which act as effective urease inhibitors with very low cytotoxicity. One compound (b19) was evaluated in detail and shows promising features for further development as an agent to treat H. pylori caused diseases. Excellent values for the inhibition of b19 against both extracted urease and urease in intact cell were observed, which shows IC50 values of 0.16 ± 0.05 and 3.86 ± 0.10 µM, being 170- and 44-fold more potent than the clinically used drug AHA, respectively. Docking simulations suggested that the monosubstituted thiourea moiety penetrates urea binding site. In addition, b19 is a rapid and reversible urease inhibitor, and displays nM affinity to urease with very slow dissociation (koff=1.60 × 10-3 s-1) from the catalytic domain.

DIProT: A deep learning based interactive toolkit for efficient and effective Protein design.

The protein inverse folding problem, designing amino acid sequences that fold into desired protein structures, is a critical challenge in biological sciences. Despite numerous data-driven and knowledge-driven methods, there remains a need for a user-friendly toolkit that effectively integrates these approaches for in-silico protein design. In this paper, we present DIProT, an interactive protein design toolkit. DIProT leverages a non-autoregressive deep generative model to solve the inverse folding problem, combined with a protein structure prediction model. This integration allows users to incorporate prior knowledge into the design process, evaluate designs in silico, and form a virtual design loop with human feedback. Our inverse folding model demonstrates competitive performance in terms of effectiveness and efficiency on TS50 and CATH4.2 datasets, with promising sequence recovery and inference time. Case studies further illustrate how DIProT can facilitate user-guided protein design.

Comprehensive analysis and prognostic assessment of senescence-associated genes in bladder cancer.

BACKGROUND: The prevalence and mortality of bladder cancer (BLCA) present a significant medical challenge. While the function of senescence-related genes in tumor development is recognized, their prognostic significance in BLCA has not been thoroughly explored. METHODS: BLCA transcriptome datasets were sourced from the TCGA and GEO repositories. Gene groupings were determined through differential gene expression and non-negative matrix factorization (NMF) methodologies. Key senescence-linked genes were isolated using singular and multivariate Cox regression analyses, combined with lasso regression. Validation was undertaken with GEO database information. Predictive models, or nomograms, were developed by merging risk metrics with clinical records, and their efficacy was gauged using ROC curve methodologies. The immune response's dependency on the risk metric was assessed through the immune phenomenon score (IPS). Additionally, we estimated IC50 metrics for potential chemotherapeutic agents. RESULTS: Reviewing 406 neoplastic and 19 standard tissue specimens from the TCGA repository facilitated the bifurcation of subjects into two unique clusters (C1 and C2) according to senescence-related gene expression. After a stringent statistical evaluation, a set of ten pivotal genes was discerned and applied for risk stratification. Validity tests for the devised nomograms in forecasting 1, 3, and 5-year survival probabilities for BLCA patients were executed via ROC and calibration plots. IC50 estimations highlighted a heightened responsiveness in the low-risk category to agents like cisplatin, cyclopamine, and sorafenib. CONCLUSIONS: In summation, our research emphasizes the prospective utility of risk assessments rooted in senescence-related gene signatures for enhancing BLCA clinical oversight.

A sensitive fluorescence sensor based on a glutathione modified quantum dot for visual detection of copper ions in real samples.

Copper (Cu2+), as a heavy metal, accumulates in the human body to a certain extent, which can induce various diseases and endanger human health. Rapid and sensitive detection of Cu2+ is highly desired. In present work, a glutathione modified quantum dot (GSH-CdTe QDs) was synthesized and applied in a "turn-off" fluorescence probe to detect Cu2+. The fluorescence of GSH-CdTe QDs could be rapidly quenched in the presence of Cu2+ through aggregation-caused quenching (ACQ), resulting from the interaction between the surface functional groups of GSH-CdTe QDs and Cu2+ and the electrostatic attraction. In the range of 20-1100 nM, the Cu2+ concentration showed a good linear relationship with the fluorescence decline of the sensor, and the LOD is 10.12 nM, which was lower than the U.S. Environmental Protection Agency (EPA) defined limit (20 µM). Moreover, aiming to attain visual analysis, colorimetric method was also used for rapidly detecting Cu2+ by capturing the change in fluorescence color. Interestingly, the proposed approach has successfully been applied for the detection of Cu2+ in real samples (i.e., environment water, food and traditional Chinese medicine) with satisfactory results, which provides a promising strategy for the detection of Cu2+ in practical application with the merits of being rapid, simple and sensitive.

Identification and Characterization of Jasmonic Acid Methyltransferase Involved in the Formation of Floral Methyl Jasmonate in Hedychium coronarium.

Hedychium coronarium is a popular ornamental flower in tropical and subtropical areas due to its elegant appearance and inviting fragrance. Methyl jasmonate (MeJA) is one of the volatile compounds in the blooming flowers of H. coronarium. However, the molecular mechanism underlying floral MeJA formation is still unclear in H. coronarium. In this study, a total of 12 SABATH family genes were identified in the genome of H. coronarium, and their encoded proteins range from 366 to 387 amino acids. Phylogenetic analysis revealed seven clades in the SABATH family and a JMT ortholog clade, including two HcSABATH members. Combined with expression profiling of HcSABATH members, HcJMT1 was identified as the top candidate gene for floral MeJA biosynthesis. In vitro enzyme assays showed that HcJMT1 can catalyze the production of MeJA from jasmonic acid. Gene expression analysis indicated that HcJMT1 exhibited the highest expression in the labella and lateral petals, the major sites of MeJA emission. During flower development, the two MeJA isomers, major isomers in the products of the HcJMT1 protein, were released after anthesis, in which stage HcJMT1 displayed high expression. Our results indicated that HcJMT1 is involved in the formation of floral MeJA in H. coronarium.

Rapid identification of the geographical origin of Eucommia ulmoides by using excitation-emission matrix fluorescence combined with chemometric methods.

Eucommia ulmoides is an important and valuable traditional Chinese medicine with various medical functions, and has been widely used as health food in China, Japan, South Korea and other Asian countries for many years. The efficacy and quality of E. ulmoides are closely associated with the geographical origin. In this work, the potential of excitation-emission matrix (EEMs) fluorescence coupled with chemometric methods was investigated for simple, rapid and accurate for identification E. ulmoides from different geographical origins. Parallel factor analysis (PARAFAC) was applied for characterizing the fluorescence fingerprints of E. ulmoides samples. Moreover, k-nearest neighbor (kNN), principal component analysis-linear discriminant analysis (PCA-LDA) and partial least squares discriminant analysis (PLS-DA) models were used for the classification of E. ulmoides samples according to their geographical origins. The results showed that kNN model was more suitable for identification of E. ulmoides samples from different provinces. The kNN model could identify E. ulmoides samples from eight different geographical origins with 100% accuracy on the training and test sets. Therefore, the proposed method was available for conveniently and accurately determining the geographical origin of E. ulmoides, which can expect to be an attractive alternative method for identifying the geographic origin of other traditional Chinese medicines.

Coordinated and High-Level Expression of Biosynthetic Pathway Genes Is Responsible for the Production of a Major Floral Scent Compound Methyl Benzoate in Hedychium coronarium.

Methyl benzoate is a constituent of floral scent profile of many flowering plants. However, its biosynthesis, particularly in monocots, is scarcely reported. The monocot Hedychium coronarium is a popular ornamental plant in tropical and subtropical regions partly for its intense and inviting fragrance, which is mainly determined by methyl benzoate and monoterpenes. Interestingly, several related Hedychium species lack floral scent. Here, we studied the molecular mechanism of methyl benzoate biosynthesis in H. coronarium. The emission of methyl benzoate in H. coronarium was found to be flower-specific and developmentally regulated. As such, seven candidate genes associated with methyl benzoate biosynthesis were identified from flower transcriptome of H. coronarium and isolated. Among them, HcBSMT1 and HcBSMT2 were demonstrated to catalyze the methylation of benzoic acid and salicylic acid to form methyl benzoate and methyl salicylate, respectively. Methyl salicylate is a minor constituent of H. coronarium floral scent. Kinetic analysis revealed that HcBSMT2 exhibits a 16.6-fold lower Km value for benzoic acid than HcBSMT1, indicating its dominant role for floral methyl benzoate formation. The seven genes associated with methyl benzoate biosynthesis exhibited flower-specific or flower-preferential expression that was developmentally regulated. The gene expression and correlation analysis suggests that HcCNL and HcBSMT2 play critical roles in the regulation of methyl benzoate biosynthesis. Comparison of emission and gene expression among four Hedychium species suggested that coordinated and high-level expression of biosynthetic pathway genes is responsible for the massive emission of floral methyl benzoate in H. coronarium. Our results provide new insights into the molecular mechanism for methyl benzoate biosynthesis in monocots and identify useful molecular targets for genetic modification of scent-related traits in Hedychium.