Using Three-Dimensional Information to Predict and Interpret the Facial Selectivities of Nucleophilic Additions to Cyclic Ketones.

In this study, we devised a new method to predict facial selectivity by quantifying steric and orbital factors for the nucleophile approaching both π-plane faces. Using this method, we quantified the total electron density and frontier orbital distributions of 163 cyclic ketones with various structures and quantitatively explained the surface selectivity of 323 reactions with eight nucleophiles (BH3, LiAlH4, NaBH4, LiAl(OMe)3H, MeLi, MeMgI, PhLi, and PnMgI). Importance analysis showed a large orbital effect for BH3, LiAlH4, and NaBH4 and the dominance of the steric effect for LiAl(OMe)3H, MeLi, MeMgI, PhLi, and PhMgI. Our method analyzes three-dimensional features based on Gaussian cube files, which can be easily obtained using mainstream computational chemistry software packages, and this approach should prove useful for predicting the rates and facial selectivity of other reactions.

Compound Classification and Consideration of Correlation with Chemical Descriptors from Articles on Antioxidant Capacity Using Natural Language Processing.

In recent times, there has been a substantial increase in the number of articles focusing on antioxidants. However, the development of a comprehensive estimator for antioxidant capacity remains elusive due to the challenge of integrating information from these articles. Furthermore, the complexity of the antioxidant mechanism, which involves a multitude of factors, makes it difficult to establish a simple equation or correlation. Hence, there is a pressing need for a model that can effectively interpret the collective knowledge from these articles, especially from a chemistry perspective. In this research, we employed natural language processing techniques, specifically Word2Vec, to analyze articles related to antioxidant capacity. We extracted representation vectors of compound names from these documents and organized them into 10 distinct clusters. In our investigation of two of these clusters, we unveiled that the majority of the compounds in question were flavonoids and flavonoid glycosides. To establish a link between the descriptors and clusters, we utilized kernel density estimation and generated scatter plots to visualize their similarity. These visualizations clearly indicated a strong relationship between the descriptors and clusters, affirming that a tangible connection exists between word vectors and compound descriptors through a document analysis conducted with natural language processing techniques. This study represents a pioneering approach that utilizes document analysis to shed light on the field of antioxidant capacity research, marking a significant advancement in this domain.

Feature Selection for the Interpretation of Antioxidant Mechanisms in Plant Phenolics.

Antioxidants, represented by plant phenolics, protect living tissues by scavenging reactive oxygen species through diverse reaction mechanisms. Research on antioxidants is often individualized, for example, focusing on the evaluation of their activity against a single reactive oxygen species or examining the antioxidant properties of compounds with similar structures. In this study, multivariate analysis was used to comprehensively examine antioxidant properties. Eighteen features were selected to explain the results of the antioxidant capacity tests. These selected features were then evaluated by supervised learning, using the results of the antioxidant capacity assays. Dimension-reduction techniques were also used to represent the compound space with antioxidants as a two-dimensional distribution. A small amount of data obtained from several assays provided us with comprehensive information on the relationships between the structures and activities of antioxidants.

Development of novel deep multimodal representation learning-based model for the differentiation of liver tumors on B-mode ultrasound images.

BACKGROUND AND AIM: Recently, multimodal representation learning for images and other information such as numbers or language has gained much attention. The aim of the current study was to analyze the diagnostic performance of deep multimodal representation model-based integration of tumor image, patient background, and blood biomarkers for the differentiation of liver tumors observed using B-mode ultrasonography (US). METHOD: First, we applied supervised learning with a convolutional neural network (CNN) to 972 liver nodules in the training and development sets to develop a predictive model using segmented B-mode tumor images. Additionally, we also applied a deep multimodal representation model to integrate information about patient background or blood biomarkers to B-mode images. We then investigated the performance of the models in an independent test set of 108 liver nodules. RESULTS: Using only the segmented B-mode images, the diagnostic accuracy and area under the curve (AUC) values were 68.52% and 0.721, respectively. As the information about patient background and blood biomarkers was integrated, the diagnostic performance increased in a stepwise manner. The diagnostic accuracy and AUC value of the multimodal DL model (which integrated B-mode tumor image, patient age, sex, aspartate aminotransferase, alanine aminotransferase, platelet count, and albumin data) reached 96.30% and 0.994, respectively. CONCLUSION: Integration of patient background and blood biomarkers in addition to US image using multimodal representation learning outperformed the CNN model using US images. We expect that the deep multimodal representation model could be a feasible and acceptable tool for the definitive diagnosis of liver tumors using B-mode US.

Identification of liver fibrosis using the hepatic vein waveform in patients with Fontan circulation.

AIM: Liver fibrosis caused by congestive hepatopathy has emerged as an important complication after Fontan procedure. We evaluated the utility of the hepatic vein (HV) waveform using Doppler ultrasound for identification of liver fibrosis in Fontan patients. METHODS: We investigated the HV waveforms in 41 Fontan patients and assessed correlations with clinical parameters, liver fibrosis markers, and hemodynamic data. RESULTS: Based on our preliminary analysis of 64 adult patients with chronic liver disease who underwent liver biopsy, we classified HV waveforms into five types with reference to the degree of flattening (from type 1, normal triphasic waveform; to type 5, a monophasic waveform indicating cirrhosis), and confirmed a significant correlation between waveform pattern and fibrosis stage. Notably, we detected HV waveforms in all of the Fontan patients and classified them into five types. The HV waveform pattern positively correlated with γ-glutamyl transferase and hyaluronic acid levels, and negatively correlated with albumin level and platelet count, but did not correlate with central venous pressure or brain natriuretic peptide level, suggesting that HV waveform could reflect pathophysiological changes in the liver without being affected by hepatic congestion. The highest area under the receiver operating characteristic curve of the HV waveform for detecting advanced liver fibrosis, as defined by ultrasonic findings and clinical features, was 0.829 (81.8% sensitivity, 73.3% specificity), which was higher than that of other non-invasive fibrosis markers. CONCLUSIONS: Hepatic vein waveforms change in accordance with liver fibrosis progression in Fontan patients, and can be a useful indicator of liver fibrosis after the Fontan procedure.

Two Reaction Mechanisms via Iminium Ion Intermediates: The Different Reactivities of Diphenylprolinol Silyl Ether and Trifluoromethyl-Substituted Diarylprolinol Silyl Ether.

The reactions of α,ß-unsaturated aldehydes with cyclopentadiene in the presence of diarylprolinol silyl ethers as catalyst proceed via iminium cations as intermediates, and can be divided into two types; one involving a Michael-type reaction (type A) and one involving a cycloaddition (type B). Diphenylprolinol silyl ethers and trifluoromethyl-substituted diarylprolinol silyl ethers, which are widely used proline-type organocatalysts, have been investigated in this study. As the LUMO of the iminium ion derived from trifluoromethyl-substituted diarylprolinol silyl ether is lower in energy than that derived from diphenylprolinol silyl ether, as supported by ab initio calculations, the trifluoromethyl-substituted catalyst is more reactive in a type B reaction. The iminium ion from an α,ß-unsaturated aldehyde is generated more quickly with diphenylprolinol silyl ether than with the trifluoromethyl-substituted diarylprolinol silyl ether. When the generation of the iminium ion is the rate-determining step, the diphenylprolinol silyl ether catalyst is the more reactive. Because acid accelerates the generation of iminium ions and reduces the generation of anionic nucleophiles in the Michael-type reaction (type A), it is necessary to select the appropriate acid for specific reactions. In general, diphenylprolinol silyl ether is a superior catalyst for type A reactions, whereas the trifluoromethyl-substituted diarylprolinol silyl ether catalyst is preferred for type B reactions.

Potential associations between perihepatic lymph node enlargement and liver fibrosis, hepatocellular injury or hepatocarcinogenesis in chronic hepatitis B virus infection.

AIM: Although perihepatic lymph node enlargement (PLNE) is frequently observed in chronic liver disease, little is known about PLNE in chronic hepatitis B virus (HBV) infection. We aimed to evaluate this issue. METHODS: We originally enrolled a consecutive 502 patients with chronic HBV infection. Among them, 288 patients without history of interferon-based or nucleoside analog treatment and hepatocellular carcinoma (HCC) were primarily analyzed. RESULTS: PLNE was detected in 27 of 288 (9.4%) patients, which was fewer than that in chronic hepatitis C patients but more than that in subjects undertaking a general health examination as previously reported. The presence of PLNE was significantly associated with a higher probability of having an aspartate aminotransferase (AST) platelet ratio index of more than 1.5 (11.1% vs 1.5%, P = 0.01), a higher AST level (38.0 vs 26.8 U/L, P = 0.001), a higher alanine aminotransferase level (50.1 vs 28.0 U/L, P < 0.0001), and a lower platelet count (18.6 vs 20.6 × 10(4) /µL, P = 0.048) after adjustment for sex and age. However, in our original sample (n = 502), PLNE was observed in 1.4% of the patients with HCC and/or its history whereas 9.2% of the patients without HCC, and the proportion was significantly lower in patients with HCC and/or its history (P = 0.03). CONCLUSION: PLNE was associated with liver fibrosis and hepatocellular injury, but was negatively associated with HCC in chronic HBV infection.

A theoretical and experimental study of the effects of silyl substituents in enantioselective reactions catalyzed by diphenylprolinol silyl ether.

The effect of silyl substituents in diphenylprolinol silyl ether catalysts was investigated. Mechanistically, reactions catalyzed by diphenylprolinol silyl ether can be categorized into three types: two that involve an iminium ion intermediate, such as for the Michael-type reaction (type A) and the cycloaddition reaction (type B), and one that proceeds via an enamine intermediate (type C). In the Michael-type reaction via iminium ions (type A), excellent enantioselectivity is realized when the catalyst with a bulky silyl moiety is employed, in which efficient shielding of a diastereotopic face of the iminium ion is directed by the bulky silyl moiety. In the cycloaddition reaction of iminium ions (type B) and reactions via enamines (type C), excellent enantioselectivity is obtained even when the silyl group is less bulky and, in this case, too much bulk reduces the reaction rate. In other cases, the yield increases when diphenylprolinol silyl ethers with bulky substituents are employed, presumably by suppressing side reactions between the nucleophilic catalyst and the reagent. The conformational behaviors of the iminium and enamine species have been determined by theoretical calculations. These data explain the effect of the bulkiness of the silyl substituent on the enantioselectivity and reactivity of the catalysts.

DPPH Measurements and Structure-Activity Relationship Studies on the Antioxidant Capacity of Phenols.

The consumption of foods that are high in antioxidant capacity is believed to contribute to good health. Moreover, the addition of highly antioxidant compounds to foods is believed to prevent food deterioration. Among the known antioxidants in food, phenols have been identified as the primary antioxidants. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay is a simple, inexpensive, and rapid method widely used to evaluate the antioxidant capacity. Although the results of the DPPH assay depend on conditions such as the reaction time and concentration, the experimental conditions have not been standardized. Further, previous research that compared the antioxidant capacity determined through the DPPH assay largely focused on the differences in the specific substructures of approximately several dozen compounds. In this study, we conducted DPPH assays on 169 phenols under the same experimental conditions and summarized the correlation between their structures and activity. This DPPH assay study is the first single-laboratory investigation of the largest number of components in terms of their Trolox equivalent antioxidant capacities. Further, the analysis method was reproduced in an interlaboratory collaborative study, enabling its application in the reproduction and comparison of measurements in other laboratories.

Diagnostic performance of two-dimensional shear wave elastography and attenuation imaging for fibrosis and steatosis assessment in chronic liver disease.

PURPOSE: We investigated the diagnostic performance of two-dimensional shear wave elastography (2D-SWE) and attenuation imaging (ATI) in detecting fibrosis and steatosis in patients with chronic liver disease (CLD), comparing them with established methods. METHODS: In 190 patients with CLD, 2D-SWE and vibration-controlled transient elastography (VCTE) were used for liver stiffness measurement (LSM), and ATI and controlled attenuation parameter (CAP) were used for steatosis quantification. The correlations between these new and established methods were analyzed. RESULTS: Significant correlations were found between 2D-SWE and VCTE (r = 0.78, P < 0.001), and between ATI and CAP (r = 0.70, P < 0.001). Liver stiffness tended to be lower with 2D-SWE compared with that with VCTE, especially in cases with higher LSM, and ATI was less influenced by skin-capsular distance than CAP. Area under the receiver-operating characteristics curves (AUCs) and optimal cut-offs of 2D-SWE for diagnosing liver fibrosis stages F2, F3, and F4 were 0.73 (8.7 kPa), 0.79 (9.1 kPa), and 0.88 (11.6 kPa), respectively. The AUCs and optimal cut-offs of ATI for diagnosing hepatic steatosis grades S1, S2, and S3 were 0.91 (0.66 dB/cm/MHz), 0.80 (0.79 dB/cm/MHz), and 0.88 (0.86 dB/cm/MHz), respectively. A subgroup analysis of 86 patients with metabolic dysfunction-associated steatotic liver disease also demonstrated good performance for 2D-SWE and ATI. CONCLUSION: 2D-SWE and ATI performed comparably with conventional VCTE and CAP in evaluating CLD, offering reliable alternatives for diagnosing liver fibrosis and steatosis.

Perihepatic lymph node enlargement observed at a general health examination: A cross-sectional study.

AIM: Although perihepatic lymph node enlargement (PLNE) is known as a common finding in chronic liver disease, it can be found occasionally at a general health examination. We aimed to clarify the clinical significance of PLNE in general. METHODS: Between January 2008 and December 2011, 4234 subjects were enrolled, who underwent a general health examination at the University of Tokyo Hospital. RESULTS: PLNE was observed in 69 (1.6%) subjects, among whom 17 (0.4%) had liver disorders and 13 (0.3%) had malignancy, one of whom had both. No disorders were determined in the remaining 40 subjects (0.9%). Among 17 subjects with liver disorder-associated PLNE, anti-hepatitis C virus (HCV) antibody was determined in 11 and serum alanine aminotransferase levels were less than 40 U/L in eight. Among 13 subjects with malignancy-associated PLNE, para-aortic lymph nodes were also enlarged in eight. Among 40 subjects with PLNE of unknown etiology, 27 could be followed up for the mean period of 2.08 years, where no underlying disorders were newly determined with largely unaltered size of PLNE. CONCLUSION: The incidence of PLNE in the general population may vary with the prevalence of chronic liver disease, especially HCV infection. When PLNE is observed, liver disorders should be first surveyed including HCV infection even with normal serum alanine aminotransferase levels. PLNE with para-aortic lymph node enlargement may be suggestive of a malignant lesion. The incidence of PLNE of unknown etiology may be approximately 1% in the general population, which may be just followed up without further change.

Perihepatic lymph node enlargement is a negative predictor for sustained responses to pegylated interferon-α and ribavirin therapy for Japanese patients infected with hepatitis C virus genotype 1.

AIM: Although perihepatic lymph node enlargement (PLNE) is reportedly associated with the negative outcome of interferon therapy for chronic hepatitis C, there were limitations in that the results were obtained in patients with various genotypes, viral loads and treatment regimens. We aimed to precisely clarify the significance of PLNE in interferon therapy for chronic hepatitis C. METHODS: Between December 2004 and June 2005, 112 patients with hepatitis C virus (HCV) genotype 1 and HCV RNA of more than 100 KIU/mL were enrolled, who underwent pegylated interferon-α plus ribavirin therapy thereafter. PLNE was defined as a perihepatic lymph node of more than 1 cm in the longest axis by ultrasonography. RESULTS: The sustained virological response (SVR) rate was lower in patients with PLNE (4/22, 18.2%) than in those without (37/90, 41.1%; P = 0.045) and viral load decline was smaller in patients with PLNE than in those without (P = 0.028). The proportion of PLNE positive patients was the smallest in the SVR group (P = 0.033) among the patient groups divided by the treatment outcome. PLNE was retained as a negative predictor for SVR by multivariate logistic regression analysis (P = 0.012). Furthermore, PLNE was not significantly associated with the mutations at HCV core protein and at interferon sensitivity-determining region, or interleukin-28B polymorphism in 45 patients with HCV genotype 1, enrolled between December 2011 and March 2012. CONCLUSION: PLNE is a negative predictor for SVR in patients with HCV genotype 1 and HCV RNA of more than 100 KIU/mL treated with pegylated interferon-α plus ribavirin, independent of other known predictors for SVR.

New insights into the mechanism and an expanded scope of the Fe(III)-mediated vinblastine coupling reaction.

A definition of the scope of aromatic substrates that participate with catharanthine in an Fe(III)-mediated coupling reaction, an examination of the key structural features of catharanthine required for participation in the reaction, and the development of a generalized indole functionalization reaction that bears little structural relationship to catharanthine itself are detailed. In addition to providing insights into the mechanism of the Fe(III)-mediated coupling reaction of catharanthine with vindoline suggesting the reaction conducted in acidic aqueous buffer may be radical mediated, the studies provide new opportunities for the preparation of previously inaccessible vinblastine analogs and define powerful new methodology for the synthesis of indole-containing natural and unnatural products.

Hydrophilic oxygen radical absorbance capacity values of low-molecular-weight phenolic compounds containing carbon, hydrogen, and oxygen.

The antioxidant capacity of an antioxidant reflects its ability to remove reactive oxygen species (ROS). In this study, the hydrophilic oxygen radical absorbance capacity (H-ORAC) method was used to quantitatively evaluate the antioxidant capacities of natural phenols and their derivatives against peroxyl radicals. This method was comprehensively applied to low-molecular-weight phenols to construct a database. Although no macroscopic correlation was observed for values related to the antioxidant capacity expression, we observed a difference in the trend of the H-ORAC values for each functional group. Thus, this database will serve as a new benchmark and tool for molecular design.

Mechanism for the photodegradation of 9,10-dibutoxyanthracene in the presence of air.

The photoreactivity of anthracene has been previously verified for a range of its derivatives. 9,10-Dibutoxyanthracene is commonly used as an electron transfer sensitizer for photopolymerization because of its favorable optical properties. This study experimentally demonstrated that 9,10-dibutoxyanthracene produces an endoperoxide species upon reaction with the oxygen present in air. A secondary decomposition product formed during the photodecomposition of the endoperoxide species was also isolated and identified. The proposed reaction pathway is supported by singlet oxygen scavenger studies and calculations of the singlet-triplet transition energies. Our findings suggest that 9,10-dibutoxyanthracene can be used as a photo-induced oxygen scavenger.

Induced Radionuclides and Their Activity Concentration in Gel Dosimeters Irradiated by Carbon Ion Beam.

Radioactivity was measured in a micellar gel dosimeter, a polymer gel dosimeter, and water was irradiated by carbon ion beams at various beam energy conditions. Monte Carlo simulation was also performed to estimate the radioactivity. Short-lived positron-emitting nuclides were observed immediately after irradiation, but they decayed rapidly into the background. At 24 h post-irradiation, the dominant measured radioactivity was of 7Be. The simulation also showed minor activity of 24Na and 3H; however, they were not experimentally observed. The measured radioactivity was independent of the type of gel dosimeter under all irradiation conditions, suggesting that the radioactivity was induced by the interaction of carbon ions with water (the main component of the gel dosimeters). The ratio between the simulated and measured radioactivity was within 0.9-1.5. The activity concentration of 7Be was found to be less than 1/10 of the value derived using the exemption concept proposed by the International Atomic Energy Agency. This result should be applicable to irradiated gel dosimeters containing mainly water and 0-4 wt.% C and 0-1.7 wt.% N.

Organocatalytic, enantioselective intramolecular [6+2] cycloaddition reaction for the formation of tricyclopentanoids and insight on its mechanism from a computational study.

Diphenylprolinol silyl ether was found to be an effective organocatalyst for promoting the asymmetric, catalytic, intramolecular [6 + 2] cycloaddition reactions of fulvenes substituted at the exocyclic 6-position with a δ-formylalkyl group to afford synthetically useful linear triquinane derivatives in good yields and excellent enantioselectivities. The cis-fused triquinane derivatives were obtained exclusively; the trans-fused isomers were not detected among the reaction products. The intramolecular [6 + 2] cycloaddition occurs between the fulvene functionality (6π) and the enamine double bond (2π) generated from the formyl group in the substrates and the diphenylprolinol silyl ether. The absolute configuration of the reaction products was determined by vibrational circular dichroism. The reaction mechanism was investigated using molecular orbital calculations, B3LYP and MP2 geometry optimizations, and subsequent single-point energy evaluations on model reaction sequences. These calculations revealed the following: (i) The intermolecular [6 + 2] cycloaddition of a fulvene and an enamine double bond proceeds in a stepwise mechanism via a zwitterionic intermediate. (ii) On the other hand, the intramolecular [6 + 2] cycloaddition leading to the cis-fused triquinane skeleton proceeds in a concerted mechanism via a highly asynchronous transition state. (iii) The fulvene functionality and the enamine double bond adopt the gauche-syn conformation during the C-C bond formation processes in the [6 + 2] cycloaddition. (iv) The energy profiles calculated for the intramolecular reaction explain the observed exclusive formation of the cis-fused triquinane derivatives in the [6 + 2] cycloaddition reactions. The reasons for the enantioselectivity seen in these [6 + 2] cycloaddition reactions are also discussed.

Prediction and Chemical Interpretation of Singlet-Oxygen-Scavenging Activity of Small Molecule Compounds by Using Machine Learning.

A chemically explainable machine learning model was constructed with a small dataset to quantitatively predict the singlet-oxygen-scavenging ability. In this model, ensemble learning based on decision trees resulted in high accuracy. For explanatory variables, molecular descriptors by computational chemistry and Morgan fingerprints were used for achieving high accuracy and simple prediction. The singlet-oxygen-scavenging mechanism was explained by the feature importance obtained from machine learning outputs. The results are consistent with conventional chemical knowledge. The use of machine learning and reduction in the number of measurements for screening high-antioxidant-capacity compounds can considerably improve prediction accuracy and efficiency.

Catharanthine C16 substituent effects on the biomimetic coupling with vindoline: preparation and evaluation of a key series of vinblastine analogues.

The examination of the catharanthine C16 substituent effects on the Fe(III)-promoted biomimetic coupling reaction with vindoline is detailed, confirming the importance of the presence of a C16 electron-withdrawing substituent, and establishing an unanticipated unique role (>10-fold) that the C16 methyl ester plays in the expression of the natural product properties. Thus, replacement of the vinblastine C16' methyl ester with an ethyl ester (10-fold), a cyano group (100-fold), an aldehyde (100-fold), a hydroxymethyl group (1000-fold) or a primary carboxamide (>1000-fold) led to surprisingly large reductions in cytotoxic activity.

Widespread and multifocal carcinomas in situ (CISs) through almost the entire pancreas: report of a case with preoperative cytological diagnosis.

PURPOSE: It is imperative for prognostic improvement of pancreatic cancer that we try to diagnose carcinoma in situ (CIS) of lesions, i.e., precursors of invasive ductal carcinomas (IDCs) at an early stage, because results of treatment of patients with IDCs themselves continue to be rather unsatisfactory. MATERIALS AND RESULTS: We report here a case of a patient who received subtotal pancreatectomy for widespread and multifocal CISs of the pancreas after preoperative brushing cytology from the epithelium of dilated main pancreatic duct proved cancer-positive preoperatively. CONCLUSIONS: From our experience, we conclude that examination for CIS of the pancreas must be recommended whenever dilatation of relatively large pancreatic ducts is found by ultrasound or computed tomography. We should therefore advance to magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography and then cytological and/or pathological assessment of the pancreatic duct whenever non-continuous narrowing, localized dilatation, or other irregularities are encountered.