A new framework for drug-disease association prediction combing light-gated message passing neural network and gated fusion mechanism.

With the development of research on the complex aetiology of many diseases, computational drug repositioning methodology has proven to be a shortcut to costly and inefficient traditional methods. Therefore, developing more promising computational methods is indispensable for finding new candidate diseases to treat with existing drugs. In this paper, a model integrating a new variant of message passing neural network and a novel-gated fusion mechanism called GLGMPNN is proposed for drug-disease association prediction. First, a light-gated message passing neural network (LGMPNN), including message passing, aggregation and updating, is proposed to separately extract multiple pieces of information from the similarity networks and the association network. Then, a gated fusion mechanism consisting of a forget gate and an output gate is applied to integrate the multiple pieces of information to extent. The forget gate calculated by the multiple embeddings is built to integrate the association information into the similarity information. Furthermore, the final node representations are controlled by the output gate, which fuses the topology information of the networks and the initial similarity information. Finally, a bilinear decoder is adopted to reconstruct an adjacency matrix for drug-disease associations. Evaluated by 10-fold cross-validations, GLGMPNN achieves excellent performance compared with the current models. The following studies show that our model can effectively discover novel drug-disease associations.

Prenatal diagnosis of pulmonary artery sling associated with tracheal agenesis: A case report.

Pulmonary artery sling (PAS) and tracheal agenesis (TA) are rare diseases, and most cases of PAS are associated with tracheal bronchial malformations. However, PAS associated with TA is yet to be reported. We report a case of PAS with TA diagnosed prenatally. Due to the extremely low incidence, physicians do not have sufficient understanding of these diseases and it is challenging to diagnose these diseases by prenatal ultrasound, with high rates of misdiagnosis. Prenatal examination of the pulmonary artery branches, trachea, and esophagus is useful; therefore, improving the accuracy of prenatal diagnosis will help in perinatal management and counseling.

Identification of unexpected unlabeled N,N-dimethylamide formation in the synthesis of deuterated fragment of ribociclib by a HATU-mediated coupling reaction.

Starting from N,N-dimethylamine and D2 O, deuterated fragment of ribociclib was synthesized for use as a mass spectroscopy internal standard. Furthermore, systematic studies on D0 (unlabeled material) formation during the amidation reaction were performed, leading to the identification of a coupling reagent, HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), as main cause. Finally, an alternative route was designed using EDCI/HOBT as coupling reagents to produce the desired deuterated compound without D0 residue.

An efficient and facile synthesis of deuterium-labeled anticancer agent bendamustine hydrochloride.

Bendamustine hydrochloride is an alkylating agent that was developed for the treatment of various human cancers. The stable isotope-labeled bendamustine was required to support clinic studies. An effective and operationally simple method for the synthesis of [D6 ] bendamustine hydrochloride was developed using DCl as a catalyst and D2 O as a deuterium source. Under the present condition, regioselectively deuterated bendamustine hydrochloride with high deuterium incorporation is achieved.

Synthesis of obeticholic acid, a farnesoid X receptor agonist, and its major metabolites labeled with deuterium.

Simple and facile methods for the synthesis of deuterium-labeled obeticholic acid and its 2 metabolites, glycine and taurine conjugates of obeticholic acid, are described herein. The 3 deuterated compounds were applicable for use as internal standards in drug development.

An efficient synthesis of deuterium-labeled degarelix acetate, a third-generation gonadotropin-releasing hormone receptor antagonist.

Degarelix acetate, a third-generation gonadotropin-releasing hormone receptor antagonist, shows great potential in the treatment of many androgen-related diseases. To support clinical studies of degarelix acetate, deuterium-labeled degarelix is highly desired for use as an internal standard. Using D2 O/D3 PO4 as a deuterium source, 2-amino-3-(naphthalen-2-yl)propanoic acid was converted to deuterated degarelix acetate in 13 steps and in 14% overall yield.

High-Pressure and High-Temperature Synthesis and Pressure-Induced Simultaneous Optimization of the Electrical and Thermal Transport Properties of Nonstoichiometric TiO1.80.

We developed suitable high-pressure and high-temperature (HPHT) conditions for improvement of the thermoelectric properties of nonstoichiometric TiO1.80. X-ray diffraction, scanning transmission microscopy, transmission electron microscopy, and ultraviolet spectral measurements demonstrate that the crystal structures and microstructures are strongly modulated by our HPHT. The electrical properties and thermal conductivity are improved simultaneously by raising the reactive sintering pressure. The band gap was narrowed, contributing to the increase of the electrical properties with the pressure. In addition, relatively low thermal conductivities were obtained here as a result of a full spectrum of phonon scattering, benefiting from our deliberately engineered microstructures via HPHT. As a consequence, a high dimensionless figure of merit (zT) of 0.36 was obtained at 700 °C in the sample fabricated at 5 GPa. As far as we know, this is higher than all of the results of nonstoichiometric titanium oxide by other means and an enhancement of 57% of the best ever result. HPHT offers us a promising alternative for optimization of the thermoelectric properties, and it is worthwhile to popularize it.

Design, synthesis and biological evaluation of LBM-A5 derivatives as potent P-glycoprotein-mediated multidrug resistance inhibitors.

A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50>100µM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.

Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo.

The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L(-1)) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.

[The clinical analysis of plakophilin-2 gene mutation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia].

OBJECTIVE: The purpose of this study was to screen genetic variations in plakophilin-2 (PKP2) gene in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) and investigate the differences in clinical features between mutation and no-mutation groups. METHODS: Thirty unrelated Chinese patients clinically diagnosed with ARVC/D and 50 healthy controls were included. Genomic DNA was isolated from peripheral blood samples. PCR and direct sequencing were used to detect variations in PKP2 gene. RESULTS: Eight PKP2 mutant variants were identified in 10 ARVC/D patients (8 men, 2 women). Among the eight mutation, three (c.2194C>T, c. 1170+ 1G>A and c. 810_813delGGTC) were novel mutation. Clinical features of the PKP2 mutation group were similar to those of the non-mutation group. CONCLUSIONS: The rate of PKP2 mutation is 33.3% (10/30) in ARVC/D patients. The penetrance of PKP2 mutation for ARVC/D tends to be higher in man patients. No significant differences could be detected in phenotype characteristics between patients with and without PKP2 mutation.

Design, synthesis and evaluation of novel triazole core based P-glycoprotein-mediated multidrug resistance reversal agents.

A novel series of triazol-N-ethyl-tetrahydroisoquinoline based compounds were designed and synthesized via click chemistry. Most of the synthesized compounds showed P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal activities. Among them, compound 7 with little cytotoxicity towards GES-1 cells (IC50 >80µM) and K562/A02 cells (IC50 >80µM) exhibited more potency than verapamil (VRP) on increasing anticancer drug accumulation in K562/A02 cells. Moreover, compound 7 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 7 in reversing MDR revealed that it could remarkably increase the intracellular accumulation of both rhodamine-123 (Rh123) and adriamycin (ADM) in K562/A02 cells as well as inhibit their efflux from the cells. These results suggested that compound 7 showed more potency than the classical P-gp inhibitor VRP under the same conditions, which may be a promising P-gp-mediated MDR modulator for further development.

[Vitamin D3 alleviates the gastritis that associated with Helicobacter pylori infection in mice with hypercholesterolemia by enhancing the activity of vitamin D receptors in the liver tissue and blocking the signaling pathway of JAK/STAT3].

Objective To investigate whether vitamin D3 (VD3) can alleviate Helicobacter pylori (Hp) infection by reducing blood lipids and inhibiting the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Methods High-cholesterol mouse model and Hp infected mouse model were established. Each was treated with VD3 via oral administration for 8 weeks. Real-time quantitative PCR was used to detect the expression of vitamin D receptor (VDR), insulin-induced gene 2 (Insig-2), and gastrin mRNA. Western blot analysis was used to examine the expression of JAK, STAT3, and cyclooxygenase-2 (COX2) proteins in gastric tissues. Biochemical analyses were performed to measure serum cholesterol levels, and ELISA was utilized to evaluate serum gastrin, interleukin 6 (IL-6), and IL-8 levels, along with histopathological examination of liver and gastric tissues using HE staining. Results After oral administration of VD3, the levels of VDR and Insig-2 in mouse liver tissue significantly increased in the high cholesterol group and the high cholesterol combined with Hp infection group. And the expression of serum gastrin decreased. The expression of JAK, STAT3 in gastric tissues reduced, as did the expression of COX2. Serum cholesterol levels decreased, with no significant changes in IL-6 levels, but a reduction in IL-8 levels. Compared to the control group, the high cholesterol combined with Hp infection group showed reduced hepatic ballooning degeneration and alleviated gastric tissue inflammation. In addition, inflammation in gastric tissue was also reduced in the cholesterol group and the Hp infection group. Conclusion VD3 alleviates gastritis by enhancing the activity of VDR in liver tissues, blocking the JAK/STAT3 signaling pathway, and inhibiting the expression of inflammatory factors.

Multi-Kernel Graph Attention Deep Autoencoder for MiRNA-Disease Association Prediction.

Accumulating evidence indicates that microRNAs (miRNAs) can control and coordinate various biological processes. Consequently, abnormal expressions of miRNAs have been linked to various complex diseases. Recognizable proof of miRNA-disease associations (MDAs) will contribute to the diagnosis and treatment of human diseases. Nevertheless, traditional experimental verification of MDAs is laborious and limited to small-scale. Therefore, it is necessary to develop reliable and effective computational methods to predict novel MDAs. In this work, a multi-kernel graph attention deep autoencoder (MGADAE) method is proposed to predict potential MDAs. In detail, MGADAE first employs the multiple kernel learning (MKL) algorithm to construct an integrated miRNA similarity and disease similarity, providing more biological information for further feature learning. Second, MGADAE combines the known MDAs, disease similarity, and miRNA similarity into a heterogeneous network, then learns the representations of miRNAs and diseases through graph convolution operation. After that, an attention mechanism is introduced into MGADAE to integrate the representations from multiple graph convolutional network (GCN) layers. Lastly, the integrated representations of miRNAs and diseases are input into the bilinear decoder to obtain the final predicted association scores. Corresponding experiments prove that the proposed method outperforms existing advanced approaches in MDA prediction. Furthermore, case studies related to two human cancers provide further confirmation of the reliability of MGADAE in practice.

Diagnosis of Patent Foramen Ovale: The Combination of Contrast Transcranial Doppler, Contrast Transthoracic Echocardiography, and Contrast Transesophageal Echocardiography.

OBJECTIVES: To access the distinct values of contrast transcranial Doppler (cTCD), contrast transthoracic echocardiography (cTTE), and contrast transesophageal echocardiography (cTEE) in the diagnosis of right-to-left shunt (RLS) due to patent foramen ovale (PFO) and to define the most practical strategy for the diagnosis of PFO. METHODS: 102 patients with a high clinical suspicion for PFO had simultaneous cTCD, cTTE, and cTEE performed. The agitated saline mixed with blood was used to detect right-to-left shunt (RLS). RESULTS: In all 102 patients, the shunt was detected at rest by cTCD in 60.78% of cases, by cTTE in 42.16%, and by cTEE in 47.06%. The positive results of all 3 techniques with Valsalva maneuver (VM) were significantly improved. cTCD showed higher pick-up rate than cTTE (98.04% vs. 89.22%; χ 2 = 12.452, p < 0.05) and the cTEE (98.04% vs. 96.08%; nonsignificant difference) in the diagnosis of PFO. Nevertheless, cTEE, compared with cTTE, underestimated shunting in 44% of patients. The diameter of both PFO entrance and exit was significantly greater in patients with a severe shunt compared with a mild shunt (2.8 ± 1.0 mm vs. 2.0 ± 0.7 mm, t = 3.135, p < 0.05) and the cTEE (98.04% vs. 96.08%; nonsignificant difference) in the diagnosis of PFO. Nevertheless, cTEE, compared with cTTE, underestimated shunting in 44% of patients. The diameter of both PFO entrance and exit was significantly greater in patients with a severe shunt compared with a mild shunt (2.8 ± 1.0 mm vs. 2.0 ± 0.7 mm, t = 3.135, p < 0.05) and the cTEE (98.04% vs. 96.08%; nonsignificant difference) in the diagnosis of PFO. Nevertheless, cTEE, compared with cTTE, underestimated shunting in 44% of patients. The diameter of both PFO entrance and exit was significantly greater in patients with a severe shunt compared with a mild shunt (2.8 ± 1.0 mm vs. 2.0 ± 0.7 mm, t = 3.135, p < 0.05) and the cTEE (98.04% vs. 96.08%; nonsignificant difference) in the diagnosis of PFO. Nevertheless, cTEE, compared with cTTE, underestimated shunting in 44% of patients. The diameter of both PFO entrance and exit was significantly greater in patients with a severe shunt compared with a mild shunt (2.8 ± 1.0 mm vs. 2.0 ± 0.7 mm. CONCLUSIONS: The best method to diagnose PFO should be the combination of cTCD, cTTE, and cTEE. And cTCD should be applied as the first choice for screening RLS. Then, cTTE should be performed to quantify the severity of the shunt. Last but not least, cTEE should be performed to assess the morphologies of PFO when the closure is planned. The study provides for clinicians the most practical strategy for diagnosing PFO in the future. However, further trials with a large sample size are required to confirm this finding.

Discovery of a Silicon-Containing Pan-Genotype Hepatitis C Virus NS5A Inhibitor.

We describe a study leading to the discovery of compound 11, a pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with excellent potency, metabolic stability, and pharmacokinetics (PK). Compound 11 incorporating a 4-silapiperidine group was discovered by further optimizing our previous lead with a triethylsilyl moiety. It displayed great potency against genotype 1 subtype a (GT1a), -1b, -2a, -3a, -4a, -5a, and -6a with an EC50 range of 0.33-17 pM and improved potency against the resistance-associated variant GT1a_M28T. Pharmacokinetics (PK) study indicated that compound 11 has reasonable PK exposures with a high liver distribution in preclinical animal species (mouse, rat, and dog). The results of a 14 day repeat-dose toxicity study identified the safety of compound 11.

Thickness and Ratio of Noncompacted and Compacted Layers of the Left Ventricular Myocardium Evaluated in 56 Normal Fetuses by Two-Dimensional Echocardiography.

The thickness and ratio of noncompacted and compacted layers of the left ventricular (LV) myocardium in the normal fetus were investigated by fetal echocardiography. We aimed to investigate the compaction process of the LV myocardium during the normal gestation period and provide reference for echocardiographic diagnosis of a fetus with ventricular myocardium noncompaction. A total of 56 pregnant women in the gestational period of 23-30 weeks were included. Complete fetal echocardiography was performed with system ultrasonographic examination to exclude congenital heart malformation or extracardiac malformation. All 56 fetuses showed normal development. In the short-axis view of the fetal heart, the LV wall was divided into an upper and lower section at the level of the papillary muscle. Each section was then further divided into four segments, namely, anterior, posterior, lateral, and inferior wall. Thus, the LV wall was divided into eight segments. The thickness of the ventricular noncompacted and compacted layers and the ratio of the ventricular noncompacted to compacted layers of these segments at end-systole were measured and calculated. In echocardiography, the fetal LV myocardium is a two-layered structure: the endocardial noncompact myocardium (NC) with higher echo and the epicardium compact myocardium (C) with lower echo. The noncompacted layer is thinner than the compacted layer in the anterior wall, but thicker than the compacted layers in the posterior, lateral, and inferior wall. With respect to the upper and lower sections of the LV myocardium, the noncompacted layer in each segment of the upper section is thinner than that in each segment of the lower section, whereas the compacted layer of the upper section is thicker than that of the lower section. This study suggests that the densification of the fetal LV myocardium occurs gradually from base to apex and from the anterior to lateral, posterior, and inferior walls. This finding aids in further understanding the process of myocardial densification and provides a diagnostic reference for noncompaction of noncompaction cardiomyopathy (NCCM).

Quantile Score: A New Reference System for Quantitative Fetal Echocardiography Based on a Large Multicenter Study.

BACKGROUND: Normative ranges of fetal echocardiographic measurements are important for quantitative diagnosis of fetal cardiovascular disease. The current normative ranges were derived from small samples and were based on the hypothesis of a normal distribution of these measurements during fetal cardiovascular growth. The aims of this study were to test the hypothesis of a normal distribution of fetal echocardiographic measurements in a large multicenter cohort and to propose a reference system without the normal distribution hypothesis to improve accuracy of fetal echocardiographic measurements. METHODS: Fifty-two variables from 6,343 normal fetal echocardiographic examinations were acquired from seven Chinese centers. The hypothesis of a normal distribution used in ordinary least squares regression was tested with the Jarque-Bera test. The quantile score (q score) derived from quantile regression without normal distribution hypothesis was compared with the Z score derived from ordinary least squares regression. A total of 288 fetuses with outflow tract and great artery abnormalities and 300 normal fetuses were used to compare the diagnostic accuracy of q and Z scores. RESULTS: All fetal echocardiographic measurements showed non-normal distributions (P < .001). The normal range was underestimated by ordinary least squares regression compared with quantile regression by 30 ± 11%. The partial normalized areas under the receiver operating characteristic curve within the 20% false-positive rate were 0.62 and 0.50 for the q and Z scores, respectively. CONCLUSIONS: The q score provides a more robust system for determining normative ranges of fetal echocardiographic measurements. The improved sensitivity of matched false-positive rates makes the q score a more accurate reference for prenatal diagnosis, assessment, and prognosis of fetal cardiovascular disease.

High-performance liquid chromatographic determination of 2-aminoethylphosphonic acid and 2-amino-3-phosphonopropionic acid in seawater matrix using precolumn fluorescence derivatization with o-phthalaldehyde-ethanethiol.

2-Aminoethylphosphonic acid (2-AEP) and 2-amino-3-phosphonopropionic acid (2-AP3) are two types of abundant and ubiquitous naturally occurring phosphonates used as sources of phosphorus by many prokaryotic lineages. The potential utilization mechanism of 2-AEP and 2-AP3 in eukaryotic phytoplankton is currently under investigation. However, the lack of suitable analytical methods in saline samples are the limitation of such researches. Herein, a high-performance liquid chromatography (HPLC) method for monitoring 2-AEP and 2-AP3 using precolumn fluorescence derivatization with o-phthalaldehyde-ethanethiol (OPA-ET) in seawater matrix was developed. The derivatization procedure and HPLC conditions were carefully examined, which included optimization of the fluorescence excitation and emission wavelengths, the ammonium acetate concentration and pH of the mobile phase, the OPA-ET reagent content and composition and derivatization time. Because increasing salinity was observed to lower the derivatization efficiency, working standards were freshly prepared in artificial seawater with the same salinity as that of the samples for the quantification of 2-AEP and 2-AP3. The developed HPLC method showed a wide linear response with high linearity (R2 > 0.999) and high repeatability at three concentration levels. The relative standard deviation was less than 4.1% for 2-AEP and less than 1.7% for 2-AP3 (n = 7). The limits of detection for 2-AEP and 2-AP3 in artificial seawater matrix were both 12.0 µg/L. The recoveries were 83.0-104% for 2-AEP and 72.6-98.6% for 2-AP3 in different aqueous samples, including algal culture medium prepared with filtered seawater. These results indicated the matrix effect of this method was insignificant.

Design, synthesis and identification of silicon-containing HCV NS5A inhibitors with pan-genotype activity.

Modification of a HCV NS5A inhibitor, ombitasvir, led to the identification of 10d with improved pan-genotype NS5A inhibition and better pharmacokinetic properties. The key structural changes to ombitasvir include bioisosteric replacement of carbon with silicon atom. Compared with ombitasvir, the activity of anti-HCV genotypes (GT 1 to 6) of 10d is increased to some extent, especially the inhibitory activity against genotype 3a and 6a is increased by more than seven times, and the dog's in vivo pharmacokinetics properties were also superior to ombitasvir. Further drug evaluation showed that 10d was similar to ombitasvir on plasma protein binding and liver distribution profiles, with no cytotoxicity and no inhibitory effect on both CYP 450 and hERG ligand binding. However, permeability assay results indicated that 10d was not the substrate of P-gp or BCRP transporter, which is different from that of ombitasvir. The results of a 14-day repeat-dose toxicity study identified no toxicity with 10d. Our findings in preclinical tests suggest that the silicon-containing compound 10d could be worthy of continued study as a potential drug candidate.