Trends in under-five mortality rate in China, 1996-2020: a Joinpoint regression and correlation analysis.

OBJECTIVES: To analyse annual trends of the under-five mortality rate (U5MR) and main cause-specific U5MR in China from 1996 to 2020 and to assess the potential correlation of the healthcare system and health expenditure with the U5MR in China. DESIGN: A retrospective observational study using national data from 1996 to 2020. Joinpoint regression was employed to model U5MR trends and Pearson correlation analysis was conducted to examine the relationship between healthcare system factors, health expenditure and U5MR. SETTING: Nationwide study covering both rural and urban populations across China over a 25-year period. RESULTS: The U5MR in China experienced a three-stage decline from 1996 to 2020 with an average annual percentage rate change (AAPC) of -7.27 (p<0.001). The AAPC of the rural U5MR (-7.07, p<0.001) was higher than that in urban areas (-5.57, p<0.001). Among the five main causes, the decrease in pneumonia-caused U5MR was the fastest while the decreases in congenital heart disease and accidental asphyxia were relatively slow. The rates of hospital delivery (r=-0.981, p<0.001), neonatal visits (r=-0.848, p<0.001) and systematic health management (r=-0.893, p<0.001) correlated negatively with U5MR. The proportion of government health expenditure in the total health expenditure (THE) correlated negatively with the national U5MR (r=-0.892, p<0.001) while the proportion of out-of-pocket health expenditure in THE correlated positively (r=0.902, p<0.001). CONCLUSION: China made significant advances in reducing U5MR from 1996 to 2020. The rural-urban gap in U5MR has narrowed, though rural areas remain a key concern. To further reduce U5MR, China should focus on rural areas, pay more attention to congenital heart disease and accidental asphyxia, further improve its health policies, and continue to increase the government health expenditure.

Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation for identification of potential ERK inhibitors.

As the downstream component of the mitogen-activated protein kinases (MAPK) pathway, the extracellular signal-regulated kinase (ERK) is responsible for phosphorylating a broad range of substrates in cell proliferation, differentiation, and survival. Direct targeting the ERK proteins by the piperidinopyrimidine urea-based inhibitors has been demonstrated to be an effective way to block the MAPK signaling pathway in inhibiting tumor growth. In order to discover better inhibitors, a computer-aided drug design (CADD) approach was employed to reveal the pharmacological characteristics and mechanisms of action. The pharmacophore model was generated on the basis of the compounds with eight features, i.e., four hydrogen bond acceptor atoms, one hydrogen bond donor atom, and three hydrophobic centers. A total of 14 hit compounds were obtained through virtual screening. Two potential inhibitors, namely VS01 and VS02, have been identified by molecular docking and molecular dynamics simulations. Both compounds are capable of attaching to the ERK pocket precisely. The binding free energies of VS01 and VS02 are about 15 kJ/mol and 4 kJ/mol stronger than that of the clinic Ulixertinib because of the characteristic hydrogen bonding, electrostatic, and hydrophilic interactions. The present theoretical investigations shed new light on the rational design of the potential ERK inhibitors to stimulate further experimental tests.Communicated by Ramaswamy H. Sarma.

Computational Investigations on Reaction Mechanisms of the Covalent Inhibitors Ponatinib and Analogs Targeting the Extracellular Signal-Regulated Kinases.

As an important cancer therapeutic target, extracellular signal-regulated kinases (ERK) are involved in triggering various cellular responses in tumors. Regulation of the ERK signaling pathway by the small molecular inhibitors is highly desired for the sake of cancer therapy. In contrast to the routine inhibitors targeting ERKs through long-range non-bonding interactions, Ponatinib, a covalent inhibitor to ERK2 with a macrocyclic structure characterized by the α,ß-C=C unsaturated ketone, can form the stable -C(S)-C(H)-type complex via the four-center barrier due to the nucleophilic addition reaction of the thiol group of the Cys166 residue of ERK2 with the C=C double bond of Ponatinib with reaction free-energy barrier of 47.2 kcal/mol. Reaction mechanisms for the covalent binding were calculated using QM/MM methods and molecular dynamics simulations. The interaction modes and the corresponding binding free energies were obtained for the non-covalent and covalent complexation. The binding free energies of the non-covalent and covalent inhibitions are 14.8 kcal/mol and 33.4 kcal/mol, respectively. The mechanistic study stimulated a rational design on the modified Ponatinib structure by substituting the C=C bond with the C=N bond. It was demonstrated that the new compound exhibits better inhibition activity toward ERK2 in term of both thermodynamic and kinetic aspects through the covalent binding with a lower reaction free-energy barrier of 23.1 kcal/mol. The present theoretical work sheds new light on the development of the covalent inhibitors for the regulation of ERKs.

Two-Dimensional Ultrasound and Triplane Tissue Doppler Ultrasound of Patients with Severe Preeclampsia.

This study was to investigate the cardiac function characteristics under two-dimensional ultrasound and triplane tissue Doppler imaging (TDI) of patients with severe preeclampsia (SPE). 28 SPE patients with singleton pregnancy from January 2018 to December 2020 were included in the SPE group. 25 healthy nonpregnant women of reproductive age were taken as the control group (Ctrl group), and 26 normal pregnant women with singleton pregnancy were selected as the normal group (Norm group); all the research objects underwent ultrasonography. The morphological and functional indexes of left and right ventricles were compared among the cases in different groups. The results showed that the left ventricular end-diastolic period diameter (LVEDd), left ventricular relative wall thickness (LV-RWT), left ventricular mass index (LVMi), left anterior descending (LAd), left ventricular E/e and e/a values, right ventricular diameter (RV-D), right ventricular anterior wall thickness (RVAW), a value, right atrial septum (RA-S), pulmonary artery systolic pressure (PASP), left ventricular end-systolic period diameter (LVEds), interventricular septal thickness (IVSd), posterior wall thickness (PWd), end-diastolic period volume (EVD), end-systolic period volume (ESV), relative wall thickness (RWT), sphericity index (SpI), left atrium volume index (LAVi), and E/e value of patients in the SPE group were higher than those in the Ctrl group and the Norm group (P < 0.05). The mitral annular plane systolic excursion (MAPSE), s value, tricuspid annual plane systolic excursion (TAPSE), ratio of early diastolic blood flow velocity to late diastolic blood flow velocity (E/A), ratio of peak early diastolic velocity to peak late diastolic velocity (e/a), peak early diastolic velocity (e), and ejection fraction (EF) of the SPE group were lower than those of the Ctrl group and the Norm group (P < 0.05). The ratio of mitral valve early diastolic blood flow velocity to peak early diastolic velocity (E/e) of the Norm group was higher than that of the Ctrl group (P < 0.05). In two-dimensional ultrasound of the SPE group, the maximum difference in time from the start to the peak of systole (Ts) of the right ventricle between the basal and middle segments of the lateral wall and that of interventricular septum (RV-Ts-max) was 31.56 ± 0.39%. The maximum difference in time to peak of early diastole (Te) under the same condition (RV-Te-max) was 47.16 ± 0.19%. Left ventricular LV-Ts-max and LV-Te-max were 9.83 ± 0.80% and 8.37 ± 0.68%, respectively, in triplane TDI, which were considerably higher than those in the Ctrl and Norm groups (P < 0.05). It suggested that two-dimensional ultrasound and triplane TDI could reflect the ventricular morphology as well as diastolic and systolic function injury in patients, which offered a reference basis for the diagnosis of SPE.

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines.

A novel series of dihydrofuro[3,4-d]pyrimidine (DHPY) analogs have recently been recognized as promising HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with potent antiviral activity. To better understand the pharmacological essentiality of these DHPYs and design novel NNRTI leads, in this work, a systematic in silico study was performed on 52 DHPYs using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, virtual screening, absorption-distribution-metabolism-excretion (ADME) prediction, and molecular dynamics (MD) methods. The generated 3D-QSAR models exhibited satisfactory parameters of internal validation and well-externally predictive capacity, for instance, the q2, R2, and r pred 2 of the optimal comparative molecular similarity indices analysis model were 0.647, 0.970, and 0.751, respectively. The docking results indicated that residues Lys101, Tyr181, Tyr188, Trp229, and Phe227 played important roles for the DHPY binding. Nine lead compounds were obtained by the virtual screening based on the docking and pharmacophore model, and three new compounds with higher docking scores and better ADME properties were subsequently designed based on the screening and 3D-QSAR results. The MD simulation studies further demonstrated that the newly designed compounds could stably bind with the HIV-1 RT. These hit compounds were supposed to be novel potential anti-HIV-1 inhibitors, and these findings could provide significant information for designing and developing novel HIV-1 NNRTIs.

A NMR-based drug screening strategy for discovering active substances from herbal medicines: Using Radix Polygoni Multiflori as example.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicines have always been important sources for new drugs. And developing new drugs from traditional herbal medicine is currently still an effective way. However, screening for active substances from herbal medicines extracts has ever been a challenging topic, due to their intrinsic complexity. The herb Radix Polygoni Multiflori has been used as a tonic and an antiaging herb in Traditional Chinese Medicine. In clinical studies, the extract of Radix Polygoni Multiflori can improve hypercholesterolemia, atherosclerotic, diabetes and other diseases commonly associated with glycolipid metabolism, however, the molecular mechanisms of these actions are unknown. AIM OF THE STUDY: We devised a NMR-based drug screening strategy for discovering active substances from herbal medicines, using Radix Polygoni Multiflori as example to address such challenging topic, meanwhile, to explore molecular target of Radix Polygoni Multiflori's glycolipid metabolism benefit. MATERIALS AND METHODS: Herbal medicines extracts were subjected to moderate separation to generate libraries of pre-purified subfractions, target protein was then added to each subfraction, and ligand-observed NMR experiments (line-broadening experiment, chemical shift perturbations measurements and saturation transfer difference spectrum) were performed, active substances identification and structural optimization were then accomplished using signals provided by ligand-observed NMR interaction detection and HPLC-SPE-NMR. The strategy was demonstrated by discovering an active component from extract of herb Radix Polygoni Multiflori, using human fatty acid binding protein 4 (FABP4) as target protein. RESULTS: 2,4-dihydroxy-6-[(1E)-2-(4-hydroxyphenyl)ethenyl]phenyl-ß-D-glucopyranoside(TSG), the hit from one subfraction, has obvious interaction with target protein FABP4, due to FABP4 is a potential therapeutic target for metabolic diseases such as diabetes and atherosclerosis, the screening result will give clue to the active component and molecular target of Radix Polygoni Multiflori's glycolipid metabolism benefit. Besides, interaction information at atom level offered by ligand-observed NMR experiment would be valuable in the further stage of lead optimization. CONCLUSIONS: The devised NMR-based drug screening strategy can discover active substances from herbal medicines efficiently and precisely, meanwhile, can shed light on molecular mechanism of traditional usage of the herb.

Identification of The Fipronil Resistance Associated Mutations in Nilaparvata lugens GABA Receptors by Molecular Modeling.

Fipronil, as the first commercialized member of phenylpyrazole insecticides, has been widely used to control planthoppers in China due to its high insecticidal activity and low toxicity to mammals. However, insects have developed resistance to phenylpyrazoles after their long-term use. The resistance mechanism of insects to fipronil has not been well identified, which limited the development of phenylpyrazole insecticides. In the present study, we aimed to elucidate the related fipronil-resistance mechanism in N. lugens GABA receptors by homology modeling, molecular docking, and molecular dynamics. The results indicated that fipronil showed the weakest interaction with the mutant (R0'Q + A2'S) GABA receptors, which is consistent with the experimental study. The binding poses of fipronil were found to be changed when mutations were conducted. These findings verified the novel fipronil-resistance mechanism in silico and provide important information for the design of novel GABAR-targeting insecticides.

In silico studies of diarylpyridine derivatives as novel HIV-1 NNRTIs using docking-based 3D-QSAR, molecular dynamics, and pharmacophore modeling approaches.

A series of novel diarylpyridine derivatives has recently been identified as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), and most of them exhibited potent activities against HIV-1 strains, with EC50 values in the low nanomolar range. However, the three-dimensional quantitative structure-activity relationships (3D-QSARs) and pharmacophore characteristics of these compounds remain to be studied. In the present study, forty-two diarylpyridine derivatives were firstly docked into HIV-1 reverse transcriptase, and molecular dynamics (10 ns) simulations were further performed to validate the reliability of the docking results, which indicated that residues Lys101, Tyr181, Tyr188, Phe227, and Trp229 might play important roles in binding with these diarylpyridines. The "U"-shaped docking conformations of all compounds were then used to construct 3D-QSAR and pharmacophore models. The satisfactory statistical parameters of CoMFA (q loo 2 = 0.665, r ncv 2 = 0.989, r pred 2 = 0.962, etc.) and CoMSIA (q loo 2 = 0.727, r ncv 2 = 0.988, r pred 2 = 0.912, etc.) models demonstrated that both constructed models had excellent predictability, and their contour maps gave insights into the structural requirements of the diarylpyridines for the anti-HIV-1 activity. A docking-conformation-based pharmacophore model, containing three hydrophobic centers, three hydrogen-bond acceptors, and three hydrogen-bond donors, was also established. The observations in this study might provide important information for the rational design and development of novel HIV-1 NNRTIs.