Azide-free cyclization reaction access to 4-aryl-NH-1,2,3-triazoles: P-toluenesulfonyl hydrazide and sulfamic acid as nitrogen sources.

An iodine-mediated cyclization has been developed to 4-aryl-NH-1,2,3-triazoles, with p-toluenesulfonyl hydrazide and sulfamic acid used as nitrogen sources. Sulfamic acid plays a crucial role in this reaction by both acting as a substrate and providing an acidic environment. This reaction offers a metal- and azide-free strategy to access NH-1,2,3-triazoles.

TfOH-Catalyzed Cascade Reaction: Metal-Free Access to 3,3-Disubstituted Phthalides from o-Alkynylbenzoic Acids.

A facile new method for the synthesis of 3,3-disubstituted phthalides is reported. A successive reaction process begins with the TfOH-catalyzed cyclization of o-alkynylbenzoic acids followed by an ortho-regioselective electrophilic alkylation of various electron-rich aromatic compounds or alkenes, which has been successfully developed. The corresponding regioselective products of 3-substituted phthalide were obtained in good to high yields.

GCKR and ADIPOQ gene polymorphisms in women with gestational diabetes mellitus.

AIMS: To investigate the associations of GCKR and ADIPOQ variants with the risk of gestational diabetes mellitus (GDM) in Chinese women. METHODS: GCKR rs1260326, ADIPOQ rs266729, and rs1501299 were selected and genotyped in 519 GDM patients and 498 controls. Candidate SNPs were genotyped using multiplex polymerase chain reaction (PCR) combined with next-generation sequencing methods, and the association of these SNPs with GDM was analyzed. RESULTS: We found that GCKR rs1260326 was significantly associated with an increased risk of GDM in the allele model, the codominant model (CC vs. TT), the dominant model, the recessive model, and the genotypic model distributions (p = 0.0029, p = 0.0022, p = 0.0402, p = 0.0038, and p = 0.0028, respectively). The rs1260326 polymorphism was shown to be associated with 1 h-OGTT level and gravidity in GDM patients (CC vs. TT: p = 0.0475 and p = 0.0220, respectively). Diastolic blood pressure (DBP) was significantly higher in the GDM patients with the rs266729 GG genotype compared to those with the CC or CG genotype (p = 0.0444 and p = 0.0339, respectively). The DBP of the GDM patients with the rs1501299 GT genotype was lower than that of those with the GG genotype (p = 0.0197). There was a weak linkage disequilibrium value between the GCKR and ADIPOQ SNPs. CONCLUSIONS: The genes GCKR and ADIPOQ may be involved in the pathophysiology of GDM.

Nomogram based on the O-RADS for predicting the malignancy risk of adnexal masses with complex ultrasound morphology.

OBJECTIVE: The accurate preoperative differentiation of benign and malignant adnexal masses, especially those with complex ultrasound morphology, remains a great challenge for junior sonographers. The purpose of this study was to develop and validate a nomogram based on the Ovarian-Adnexal Reporting and Data System (O-RADS) for predicting the malignancy risk of adnexal masses with complex ultrasound morphology. METHODS: A total of 243 patients with data on adnexal masses with complex ultrasound morphology from January 2019 to December 2020 were selected to establish the training cohort, while 106 patients with data from January 2021 to December 2021 served as the validation cohort. Univariate and multivariate analyses were used to determine independent risk factors for malignant tumors in the training cohort. Subsequently, a predictive nomogram model was developed and validated in the validation cohort. The calibration, discrimination, and clinical net benefit of the nomogram model were assessed separately by calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). Finally, we compared this model to the O-RADS. RESULTS: The O-RADS category, an elevated CA125 level, acoustic shadowing and a papillary projection with color Doppler flow were the independent predictors and were incorporated into the nomogram model. The area under the ROC curve (AUC) of the nomogram model was 0.958 (95% CI, 0.932-0.984) in the training cohort. The specificity and sensitivity were 0.939 and 0.893, respectively. This nomogram also showed good discrimination in the validation cohort (AUC = 0.940, 95% CI, 0.899-0.981), with a sensitivity of 0.915 and specificity of 0.797. In addition, the nomogram model showed good calibration efficiency in both the training and validation cohorts. DCA indicated that the nomogram was clinically useful. Furthermore, the nomogram model had higher AUC and net benefit than the O-RADS. CONCLUSION: The nomogram based on the O-RADS showed a good predictive ability for the malignancy risk of adnexal masses with complex ultrasound morphology and could provide help for junior sonographers.

[Nomogram model for predicting risk of anti-tuberculosis drug-induced liver injury among inpatients with tuberculosis].

Objective: To explore the influencing factors of anti-tuberculosis drug-induced liver injury (ATB-DILI) in hospitalized tuberculosis patients, and to establish a risk prediction model of Nomogram. Methods: A retrospective study was conducted on 5 681 tuberculosis patients admitted to Guiyang public health treatment center from January 2017 to June 2021, including 3 342 males and 2 339 females. The inpatients with ATB-DILI were selected as the case group (214 cases) and the non-ATB-DILI patients as the control group (5 427 cases). The baseline characteristics, tuberculosis condition, behavior and disease-related data of the patients were retrospectively analyzed, and the influencing factors were screened by chi-square test and multivariate logistic regression, based on which the Nomogram model was constructed and verified. The decision curve was used to evaluate the clinical application value of the model. Results: In this study, 3.8%(214/5 681) patients developed ATB-DILI. Multivariate logistic regression analysis showed that extrapulmonary tuberculosis (OR=1.876, P<0.001), malnutrition (OR=4.411, P<0.001), complicated with underlying liver disease (OR=4.961, P<0.001) and intermittent use of hepatoprotective drugs (OR=2.137, P=0.007) were independent risk factors for ATB-DILI, while whole-course use of hepatoprotective drugs (OR=0.292, P<0.001) was protective factor. The Nomogram model was constructed based on the above five related factors. The area under the receiver operating characteristic (ROC) curve was 0.749 (95%CI:0.713-0.786), the sensitivity was 0.640, and the specificity was 0.752, respectively. The Bootstrap method was used for internal repeated sampling for 1 000 times, the average absolute error was 0.003, the correction curve and the ideal curve were basically fitted, and the predicted values were in good agreement with the actual values. Hosmer-lemeshow test showed that the model had a good degree of fit (χ2=3.068, P=0.381). The decision curve showed that the Nomogram model had certain clinical practicability in the high risk threshold range (0.10-0.68). Conclusions: The Nomogram model for risk predicting ATB-DILI among inpatients with tuberculosis in this study has good predictability, consistency and clinical practicability, and can provide a basis for clinical prevention and control of ATB-DILI and individualized treatment in the process of anti-tuberculosis treatment.

Copper-Catalyzed Three-Component Reactions of α-Ketoaldehyde, 1,3-Dicarbonyl Compound, and Organic Boronic Acid in Water: A Route to 1,4-Diketones.

A novel three-component reaction of α-ketoaldehydes, 1,3-dicarbonyl compounds, and organic boronic acids catalyzed by CuO in water has been developed to give a wide range of products containing 1,3/1,4-diketones. The method has some advantages such as the use of readily available starting materials, wide substrate scopes, excellent yields, gram-scale synthesis, and mild reaction conditions.

Tunable Synthesis of α-Amino Boronic Esters from Available Aldehydes and Amines through Sequential One-Pot Dehydration and Copper-Catalyzed Borylacylation.

Copper-catalyzed multicomponent borylacylation of imines with acid chlorides and bis(pinacolato)diboron was developed for the preparation of synthetically useful and pharmacologically relevant α-amino boronic acid derivatives. Starting from a range of acid chlorides and imines with aryl, heteroaryl, and alkyl substituents, most of these ligand-free reactions proceeded smoothly at room temperature in moderate to good yields. Furthermore, a facile and convenient one-pot, multistep access to the direct synthesis of α-amino boronic acid derivatives from available aldehydes and amines was also developed.

Catalyst-free chemoselective α-sulfenylation/ß-thiolation for α,ß-unsaturated carbonyl compounds.

A novel, efficient, catalyst-free and product-controllable strategy has been developed for the chemoselective α-sulfenylation/ß-thiolation of α,ß-unsaturated carbonyl compounds. An aromatic sulfur group could be chemoselectively introduced at α- or ß-position of carbonyls with different sulfur reagents under slightly changed reaction conditions. A series of desired products were obtained in moderate to excellent yields. Mechanistic studies revealed that B2pin2 played the key role in activating the transformation towards the ß-thiolation of α,ß-unsaturated carbonyl compounds. This transition-metal-catalyst-free method provides a convenient and efficient tool for the highly chemoselective preparation of α-thiolation or ß-sulfenylation products of α,ß-unsaturated carbonyl compounds.

Genetic Variation of the Kalirin Gene is Associated with ICAS in the Chinese Population.

Intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of ischemic stroke (IS), especially in recurrent patients. Several studies have demonstrated an intimate association between the genetic mutation of the KALRN gene and IS. The main aim of this study was to clarify the relationship between three single nucleotide polymorphisms (SNPs) of KALRN and ICAS in a northern Chinese population and further explore the underlining mechanism. The relationship between each SNP and ICAS and the related components were examined in five models (co-dominant, dominant, recessive, heterozygous, and additive). Multivariate logistic regression models were applied and adjusted for 10,000 permutation tests. Haplotype regression analysis was performed to determine the associations between haplotypes and the severity of ICAS. qRT-PCR was used to confirm the mRNA level of Kalirin. SNP rs6438833 of the Kalirin gene in the additive model was associated with ICAS (OR = 1.642, 95%CI: 1.129-2.388, PDom = 0.048). After performing 10,000 permutations, the result showed a trend toward statistical significance (Pper = 0.048). Haplotypes of the KALRN gene were not significantly associated with ICAS (global significance, p = 0.090). qRT-PCR showed that the expression of KALRN 9 in IS patients was almost threefold the control group (p < 0.0005). SNPs of the KALRN gene are associated with ICAS in the northern Chinese population.

Contrast-Enhanced Ultrasound Imaging Quantification of Adventitial Vasa Vasorum in a Rabbit Model of Varying Degrees of Atherosclerosis.

This study used an atherosclerotic rabbit model to investigate the feasibility of quantifying adventitial vasa vasorum (VV) via contrast-enhanced ultrasound (CEUS) imaging to identify early atherosclerosis. Recent evidence has linked adventitial VV with atherosclerotic plaque progression and vulnerability. A growth in VV density has been detected preceding intimal thickening and even endothelial dysfunction. In our study, carotid atherosclerosis rabbit models were used, and animals underwent CEUS imaging at the end of the atherosclerotic induction period. Normalized maximal video-intensity enhancement (MVE) was calculated to quantify VV density. After CEUS imaging, animals were euthanized, and their carotids were processed for histopathological analysis following staining for CD31 and VEGF. Adventitial normalized MVE increased as atherosclerosis progressed (p < 0.001), and normalized MVE also progressed, demonstrating a linear correlation with histological findings (r = 0.634, p < 0.001 for VEGF-positive; r = 0.538, p < 0.001 for CD31-positive). Thus, we histologically validated that CEUS imaging can be used to quantify the development of adventitial VV associated with atherosclerosis progression. This method can be used for monitoring the VV to detect early atherosclerosis.

Magnetically Retrievable Nanocomposite Based on Thiosemicarbazide-Formaldehyde Resin as a Versatile Nucleophilic Scavenger.

A magnetically retrievable nanocomposite was prepared by in situ polycondensation and entrapment of iron oxide nanoparticles. This material was found to be efficient in trapping excess electrophilic reagents such as carbonyl compounds, acid chlorides and isothiocyanates. Advantages of the new scavenger include facile preparation, high loading capacity, low cost, satisfactory swelling properties in polar solvents, and convenient magnetic recovery.

N,N-Dicarboxymethyl hydrazine: an old but neglected reagent for chemoselective derivatization of carbonyl compounds.

N,N-Dicarboxymethyl hydrazine (DCMH) was found to be a chemoselective derivatization reagent of carbonyl compounds and its potential applications in organic synthesis was investigated for the first time. DCMH could be employed as a chemoselective protective reagent of aldehydes and gave the parent aldehydes in satisfactory yields. In proof-of-concept systems, DCMH could play the role of a scavenger to remove aldehydes in the presence of ketones. It was also used as a tagging reagent in the selective isolation of aldehyde from the complex mixture.

Design and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors.

Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N'-substituted phenylthiourea derivatives (3a-i, 6a-k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7-tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a-i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a-k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC50=6.13 µM) is significantly higher than kojic acid (IC50=33.3 µM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor.

Real-Time Elastography Visualization and Histopathological Characterization of Rabbit Atherosclerotic Carotid Arteries.

To evaluate the feasibility of non-invasive vascular real-time elastography imaging (RTE) in visualizing the composition of rabbit carotid atherosclerotic plaque as determined by histopathology, a rabbit model of accelerated carotid atherosclerosis was used. Thirty rabbits were randomly divided into two groups of 15 rabbits each. The first group was fed a cholesterol-rich diet and received balloon-induced injury the left common carotid artery endothelium, whereas the second group only received a cholesterol-rich diet. The rabbits were all examined in vivo with HITACHI non-invasive vascular real-time elastography (Hi-RTE) at baseline and 12 wk, and results from the elastography were compared with American Heart Association histologic classifications. Hi-RTE and the American Heart Association histologic classifications had good agreement, with weighted Cohen's kappa (95% confidence internal) of 0.785 (0.649-0.920). Strains of segmented plaques that were stained in different colors were statistically different (p < 0.0001). The sensitivity and specificity of elastograms for detecting a lipid core were 95.5% and 61.5%, respectively, and the area under the receiver operating characteristic curve was 0.789, with a 95% confidence interval of 0.679 to 0.876. This study is the first to indicate the feasibility of utilizing Hi-RTE in visualizing normal and atherosclerotic rabbit carotid arteries non-invasively. This affordable and reliable method can be widely applied in research of both animal and human peripheral artery atherosclerosis.

Three-dimensional transvaginal tomographic ultrasound imaging for cervical cancer staging.

The objective of this study was to investigate the feasibility of using 3-D transvaginal tomographic ultrasound imaging (TUI) to stage patients with cervical carcinoma. Eighty women with cervical cancer who underwent transvaginal TUI examinations were enrolled. In all patients, cancer was confirmed pre-operatively by pathologic examination. Staging on the basis of clinical features, ultrasonography and magnetic resonance imaging was performed according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. Clinical, TUI and magnetic resonance imaging staging was compared with that based on histology. Depth of invasion into the stroma was measured by TUI in 52 cases and compared with pathologic results. An interclass correlation coefficient was used to analyze reproducibility. In total, all 80 patients underwent surgical treatment. The accuracy of pre-operative staging, compared with histologic findings, was 92.50% for TUI, 82.50% for magnetic resonance imaging and 78.75% for clinical examination. The mean depth of lesions as measured with TUI was 12.5 ± 6.2 mm (range: 3.5-40.0 mm), and that measured on histology was 10.5 ± 8.0 mm (range: 3.0-40.0 mm). The interclass correlation coefficient of the two methods was 0.933 (95% confidence interval: 0.887-0.961). Pre-operative TUI is promising as a method for pre-operative staging of cervical carcinomas. TUI can also reliably assess lesion depth.

KALRN Rare and Common Variants and Susceptibility to Ischemic Stroke in Chinese Han Population.

Stroke is the second most common cause of mortality worldwide, and it is a major cause of physical disability. Several genome-wide association studies have yielded numerous common variants which increase the risk of ischemic stroke, including the Kalirin-coding gene, KALRN. KALRN strongly associates with early-onset coronary artery disease and atherosclerosis and plays an important role in stroke in the European population. In this study, we analyzed four KALRN gene SNPs in 503 ischemic stroke patients and 493 control subjects, separating the patients into separate research groups based on comorbidity with hypertension or diabetes and stroke type (atherosis or lacunar and combination type). We found a rare variant of KALRN, rs11712619, that associated with lacunar stroke in the northern Chinese Han population with an average-risk allele frequency 0.009 (OR 2.95, 95 % CI 1.08-8.01, p = 0.028). However, after adjusting for relevant factors, including sex, age, body mass index, dyslipidemia, alcohol consumption, and smoking, this association was not evident. Additionally, the KALRN variant rs6438833 was associated with ischemic stroke, ischemic stroke comorbid with diabetes, and lacunar stroke after adjusting for the relevant factors (p = 0.046, p = 0.019 and p = 0.046, respectively), which remained significant after 10,000 permutation procedure test (p' = 0.047, p' = 0.018 and p' = 0.048, respectively). The association of these rare and common variants of KALRN with ischemic stroke in northern Chinese Han population offers insight for potential therapeutic research.

Synthesis of tertiary propargylamines via a rationally designed multicomponent reaction of primary amines, formaldehyde, arylboronic acids and alkynes.

A novel approach for the synthesis of tertiary propargylamines is achieved through a Cu(OAc)2-catalyzed multicomponent reaction of primary amines, formaldehyde, arylboronic acids and alkynes, where a combination of PBM and A(3)-coupling reactions is involved in this new multicomponent reaction.

Direct olefination of benzaldehydes into 1,3-diarylpropenes via a copper-catalyzed heterodomino Knoevenagel-decarboxylation-Csp(3)-H activation sequence.

Copper-catalyzed direct olefination of benzaldehydes into 1,3-diarylpropenes by a novel domino Knoevenagel-decarboxylation-Csp(3)-H activation sequence is reported. This method provides a concise and effective route toward the synthesis of unsymmetrical 1,3-diarylpropene derivatives.

Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene rs4073259 polymorphism not associated with ischemic stroke in the northeastern Chinese Han population.

OBJECTIVE: Although recent evidence has implicated that 5-lipoxygenase activating protein (ALOX5AP) gene is associated with ischemic stroke (IS) risk, the underlying molecular mechanism remains to be defined. This study aimed to investigate the role of ALOX5AP rs4073259 in ischemic stroke in a Northeastern Chinese Han population. METHODS: A total of 501 IS patients and 497 healthy controls were enrolled for polymerase chain reaction (PCR) and ligase detection reaction (LDR) analysis of ALOX5AP rs4073259 single nucleotide polymorphism (SNP). RESULTS: There were no statistically significant differences in ALOX5AP rs4073259 allele and genotype frequencies between IS or subtypes of IS and controls. There was no significant difference in genotype and allele frequencies of atherosclerosis degree between ischemic subjects with carotid artery plaque or absence. However, total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) in women patients were significantly higher than those in men (p=0.015, 0.000, and 0.008, respectively). Total homocysteine (tHcy) was higher in men patients than that in women (p=0.021). CONCLUSION: There was no statistically significant association of ALOX5AP rs4073259 SNP with ischemic stroke in this northeastern Chinese Han population living in Heilongjiang province, China.

Pharmacophore, 3D-QSAR, and Bayesian model analysis for ligands binding at the benzodiazepine site of GABAA receptors: the key roles of amino group and hydrophobic sites.

Ligands binding at the benzodiazepine site of GABAA receptor play important pharmacological roles in clinical application. In this study, ligand-based pharmacophore modeling, 3D-QSAR analysis, and Bayesian model studies have been performed on a set of 84 diverse ligands binding at the benzodiazepine site. The results showed the best pharmacophore hypothesis AADHR.4, which included two hydrogen acceptors (A), one hydrogen donor (D), one hydrophobic group (H), and one aromatic ring (R). Atom-based 3D-QSAR model was built, and it showed good statistical significance (R(2)  = 0.936) and excellent predictive ability (Q(2)  = 0.821). Moreover, Bayesian model was developed and used to identify the key molecular features which are good or bad for the ligand binding activity. All the results from the pharmacophore, 3D-QSAR, and Bayesian modeling studies revealed that a hydrogen-bond donor (e.g., N-H) and a hydrophobic group (e.g., Br) are critical structural features for the ligands binding at the benzodiazepine site.