Global morbidity and mortality of lower respiratory infections: A population -based study.

BACKGROUND: This study provides a comprehensive, comparative and updated estimates of temporal patterns of lower respiratory infections (LRIs) globally over the past three decades. METHODS: The data on morbidity and mortality of patients with LRIs at the global, regional and national levels were retrieved from the Global Burden of Disease (GBD) 2019 study. RESULTS: Globally, the incident cases of LRIs increased from 414,342,866 [95% uncertainty interval (UI):383,529,625 to 449, 086,938]in 1990 to 488,902,504(95% UI: 457,572,987 to 522,635,542)in 2019 with the age standardized incidence rate (ASIR) decreased from 8,276/100,000 persons (95% UI: 7,727 to 8,892) to 6,295/100,000 persons (95% UI: 5,887 to 6,737) between 1990 and 2019. Number of LRIs deaths were 2,493,200 (95% UI: 2,268,184 to 2,736,184) in 2019, a decrease of 24.9% (95% UI: -34.4 to -15.4) in the past 30 years. Meanwhile, the age-standardized death rate (ASDR) declined also from 67/100,000 persons (95% UI: 61 to 73) in 1990 to 34/100,000 persons (95% UI: 31 to 38) in 2019. Moreover, the numbers and age-standardized rates per 100,000 persons of morbidity and mortality varied widely by age, sex, Socio-Demographic Index (SDI) quintiles, and geographical locations in 2019. CONCLUSION: LRIs remain a major public health concern . Some differences in age, sex, SDI quintiles, and geographical locations contribute to LRIs-related global health policy development and health system resource optimization.

Arsenic sulfide reverses cisplatin resistance in non-small cell lung cancer in vitro and in vivo through targeting PD-L1.

BACKGROUND: Recent studies have found that programmed death ligand 1 (PD-L1) might be involved in chemotherapy resistance in non-small cell lung cancer (NSCLC). Arsenic sulfide (As4 S4 ) has been recognized to have antitumor activities and enhance the cytotoxic effect of chemotherapy drugs. In this study, we aimed to verify the relationship between PD-L1 and cisplatin (DDP) resistance and identify whether As4 S4 could reverse DDP resistance through targeting PD-L1 in NSCLC. METHODS: The effect of As4 S4 and DDP on cell proliferation and apoptosis was investigated in NSCLC cell lines. The expression of p53 and PD-L1 proteins was measured by western blotting analysis. The levels of miR-34a-5p, miR-34a-3p and PD-L1 in cells were measured by real-time qPCR analysis. Mouse xenograft models were established by inoculation with A549/DDP (DDP-resistant) cells. RESULTS: Depletion of PD-L1 inhibited DDP resistance in A549/DDP and H1299/DDP cells. As4 S4 was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As4 S4 upregulated p53 expression and downregulated PD-L1 expression in A549/DDP cells. As4 S4 increased miR-34a-5p level in A549/DDP cells. Inhibition of p53 by PFT-α partially restored the levels of PD-L1 and miR-34a-5p. Pretreatment with PFT-α suppressed the apoptosis rate induced by cotreatment of As4 S4 and DDP in A549/DDP cells. Cotreatment of DDP and As4 S4 notably reduced the tumor size when compared with DDP treatment alone in vivo. CONCLUSIONS: Upregulation of PD-L1 was correlated with DDP resistance in NSCLC cells. Mechanistic analyses indicated that As4 S4 might sensitize NSCLC cells to DDP through targeting p53/miR-34a-5p/PD-L1 axis.

circSLC6A6 Sponges miR-497-5p to Promote Endometrial Cancer Progression via the PI4KB/Hedgehog Axis.

BACKGROUND: As a new kind of noncoding RNAs, circular RNAs (circRNAs) have been substantiated to be involved in multiple biological processes. Accumulating studies indicate that circular RNAs (circRNAs) regulate the development of cancers by acting as miRNA sponges. However, the role of circRNAs in endometrial cancer (EC) is rarely reported. This study was aimed at investigating the functional roles of circSLC6A6 in EC. METHODS: The qRT-PCR assay was performed to detect the circSLC6A6 expression in EC tissues and cell lines. The luciferase reporter assay was performed to explore the connection between circSLC6A6 and miR-497-5p as well as the connection between miR-497-5p and PI4KB. The colony formation assay, EdU assay, wound healing assay, and transwell assay were performed to examine the proliferation, migration, and invasion of EC cells. The in vivo assay was performed to reveal the function of circSLC6A6 in tumorigenesis. RESULTS: We found that circSLC6A6 was highly expressed in both EC tissues and cells. And circSLC6A6 promoted the proliferation, migration, and invasion of EC cells in vitro. In vivo, circSLC6A6 promoted tumor growth. Besides, a mechanistic study demonstrated that circSLC6A6 could regulate tumor-associated signaling PI4KB/hedgehog pathway by sponging miR-497-5p. CONCLUSION: This study illustrates that circSLC6A6 plays a role in promoting EC progression via the miR-497-5p-mediated PI4KB/hedgehog pathway. Our study may provide a potential novel biomarker for EC diagnosis or treatment.

Molecular docking-aided identification of small molecule inhibitors targeting ß-catenin-TCF4 interaction.

Here we report a molecular docking-based approach to identify small molecules that can target the ß-catenin (ß-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of ß-cat using publicly available ß-cat protein crystal structures, and existing ß-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to ß-cat, of which 3 were identified to be effective against a Wnt-responsive luciferase reporter. In vitro functional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the ß-cat-TCF4 PPI. GB1874 also affected the proliferation and stemness of Wnt-addicted colorectal cancer (CRC) cells in vitro. Encouragingly, GB1874 inhibited the growth of CRC tumor xenografts in vivo, thus demonstrating its potential for further development into therapeutics against Wnt-associated cancer indications.

D-dimer levels is associated with severe COVID-19 infections: A meta-analysis.

OBJECTIVE: The ongoing pandemic of COVID-19 caused by the novel coronavirus Syndrome-Coronavirus-2 (SARS-CoV-2) is an emerging, rapidly evolving situation. Excluded typical manifestation of pneumonia and acute respiratory symptoms, COVID-19 patients also have abnormal D-dimer concentration in the serum, but the results are controversial. METHOD: A meta-analysis first aims to explored the connection between D-dimer concentration and COVID-19 patients. RESULTS: Our results found a significant relationship between D-dimer and COVID-19, with a pooled OR of 1.90 (95% CI: 1.32-2.48; P < .001). The pooled data were calculated with the REM as a high heterogeneity within the studies. The sensitivity analysis results showed that the WMD ranged from 1.69 (95% CI: 1.15 to 2.23) to 2.06 (95% CI: 1.51 to 2.62) and there was no publication bias. CONCLUSIONS: Our meta-analysis showed that the severity of patients with COVID-19 significance related to D-dimer concentrations. Meanwhile, the severe COVID-19 patients tend to have a higher concentration of D-dimer when compared with non-severe patients. REVIEW CRITERIA: We used MASH word and searched the online database and followed the inclusion and exclusion standard. The detailed information can be found in the text. MESSAGE FOR THE CLINIC: Our meta-analysis showed that the severity of patients with COVID-19 significance related to D-dimer concentrations. This may be helpful for the clinic COVID-19 patients.

Systematic review and meta-analysis: the effect of bronchopulmonary dysplasia on neurodevelopment in very low birth weight premature infants.

BACKGROUND: A meta-analysis was performed to study the effect of steroid intervention on the neurodevelopment of extremely low birth weight preterm infants complicated with bronchopulmonary dysplasia, and to provide a theoretical basis for clinical treatment. METHODS: The Wanfang database, Chinese Biomedical Literature database, VIP database, Baidu Academic, CNKI database, The Cochrane Library, Medline, Embase, and PubMed database were searched by computer from establishment to 2021. Randomized controlled trials on the effect of steroids on neurodevelopment in very low birth weight preterm infants with bronchial dysplasia published from January 10, 2007 were retrieved. The included literature was evaluated for bias risk, then analyzed using RevMan 5.3 software. RESULTS: A total of 9 studies were included, with a total of 2,453 patients. The funnel plot showed that the circles and the midline of some studies were basically symmetrical, and there was no bias in the publications. The conclusions obtained were relatively reliable. Cerebral palsy, neurodevelopmental indicators, and MRI findings of preterm infants were analyzed. The cognitive impairment of very low birth weight preterm infants complicated with bronchial dysplasia (RR =0.83, 95% CI: 0.72-0.96, P=0.01) in the treatment group was significantly different from that in the control group, while cerebral palsy (RR =0.99, 95% CI: 0.75-1.29, P=0.93), speech impairment (RR =0.75, 95% CI: 0.46-1.21, P=0.24), hearing loss requiring amplification (RR =0.60, 95% CI: 0.35-1.03, P=0.06), bilateral blindness RR =0.81, 95% CI: 0.52-1.24, P=0.32), severe intraventricular hemorrhage (IVH) (RR =0.71, 95% CI: 0.33-1.50, P=0.37), and cystic periventricular leukomalacia (RR =0.82, 95% CI: 0.43-1.57, P=0.56) had no significant differences compared with the control group. DISCUSSION: In this meta-analysis, we found that the use of steroids in very low birth weight preterm infants complicated with bronchial dysplasia had significant effects on cognition, but no significant effects on hearing, vision, or language function.

A benchmarking study on virtual ligand screening against homology models of human GPCRs.

G-protein-coupled receptor (GPCR) is an important target class of proteins for drug discovery, with over 27% of FDA-approved drugs targeting GPCRs. However, being a membrane protein, it is difficult to obtain the 3D crystal structures of GPCRs for virtual screening of ligands by molecular docking. Thus, we evaluated the virtual screening performance of homology models of human GPCRs with respect to the corresponding crystal structures. Among the 19 GPCRs involved in this study, we observed that 10 GPCRs have homology models that have better or comparable performance with respect to the corresponding X-ray structures, making homology models a viable choice for virtual screening. For a small subset of GPCRs, we also explored how certain methods like consensus enrichment and sidechain perturbation affect the utility of homology models in virtual screening, as well as the selectivity between agonists and antagonists. Most notably, consensus enrichment across multiple homology models often yields results comparable to the best performing model, suggesting that ligand candidates predicted with consensus scores from multiple models can be the optimal option in practical applications where the performance of each model cannot be estimated.

Equilibrium kinetic network of the villin headpiece in implicit solvent.

We applied the single-replica multiple-state transition-interface sampling method to elucidate the equilibrium kinetic network of the 35-residue-fragment (HP-35) villin headpiece in implicit water at room temperature. Starting from the native Protein Data Bank structure, nine (meta)stable states of the system were identified, from which the kinetic network was built by sampling pathways between these states. Application of transition path theory allowed analysis of the (un)folding mechanism. The resulting (un)folding rates agree well with experiments. This work demonstrates that high (un)folding barriers can now be studied.

The association of the MTHFR c.1625A>C genetic variant with the risk of congenital heart diseases in the Chinese.

The purpose of this study is to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the risk of congenital heart diseases (CHD). The genotypes of the MTHFR genetic variant were determined by the polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Our data suggested that the allelic and genotypic frequencies of CHD patients were significantly different from non-CHD controls. The MTHFR c.1625A>C genetic variant was significantly associated with the increased risk of CHD (CC vs. AA: odds ratio [OR]=2.29, 95% confidence interval [CI] 1.15-4.53, p=0.016; C vs. A: OR=1.47, 95% CI 1.11-1.96, p=0.008). Results from this study indicate that the MTHFR c.1625A>C genetic variant influences the risk of CHD in the studied population.

Sampling the equilibrium kinetic network of Trp-cage in explicit solvent.

We employed the single replica multiple state transition interface sampling (MSTIS) approach to sample the kinetic (un)folding network of Trp-cage mini-protein in explicit water. Cluster analysis yielded 14 important metastable states in the network. The MSTIS simulation thus resulted in a full 14 × 14 rate matrix. Analysis of the kinetic rate matrix indicates the presence of a near native intermediate state characterized by a fully formed alpha helix, a slightly disordered proline tail, a broken salt-bridge, and a rotated arginine residue. This intermediate was also found in recent IR experiments. Moreover, the predicted rate constants and timescales are in agreement with previous experiments and simulations.

Isolation of cross-linked peptides by diagonal strong cation exchange chromatography for protein complex topology studies by peptide fragment fingerprinting from large sequence databases.

Knowledge of spatial proximity of amino acid residues obtained by chemical cross-linking and mass spectrometric analysis provides information about protein folding, protein-protein interactions and topology of macromolecular assemblies. We show that the use of bis(succinimidyl)-3-azidomethyl glutarate as a cross-linker provides a solution for two major analytical problems of cross-link mapping by peptide fragment fingerprinting (PFF) from complex sequence databases, i.e., low abundance of protease-generated target peptides and lack of knowledge of the masses of linked peptides. Tris(carboxyethyl)phosphine (TCEP) reduces the azido group in cross-linked peptides to an amine group in competition with cleavage of an amide bond formed in the cross-link reaction. TCEP-induced reaction products were separated by diagonal strong cation exchange (SCX) from unmodified peptides. The relation between the sum of the masses of the cleavage products and the mass of the parent cross-linked peptide enables determination of the masses of candidate linked peptides. By reversed phase LC-MS/MS analysis of secondary SCX fractions, we identified several intraprotein and interprotein cross-links in a HeLa cell nuclear extract, aided by software tools supporting PFF from the entire human sequence database. The data provide new information about interacting protein domains, among others from assemblies involved in splicing.

Adaptive single replica multiple state transition interface sampling.

The multiple state transition path sampling method allows sampling of rare transitions between many metastable states, but has the drawback that switching between qualitatively different pathways is difficult. Combination with replica exchange transition interface sampling can in principle alleviate this problem, but requires a large number of simultaneous replicas. Here we remove these drawbacks by introducing a single replica sampling algorithm that samples only one interface at a time, while efficiently walking through the entire path space using a Wang-Landau approach or, alternatively, a fixed bias. We illustrate the method on several model systems: a particle diffusing in a simple 2D potential, isomerization in a small Lennard Jones cluster, and isomerization of the alanine dipeptide in explicit water.

Conformational study of Z-Glu-OH and Z-Arg-OH: dispersion interactions versus conventional hydrogen bonding.

The gas-phase conformational preferences of the model dipeptides Z-Glu-OH and Z-Arg-OH have been studied in the low-temperature environment of a supersonic jet. IR-UV ion-dip spectra obtained using the free electron laser FELIX provide conformation-specific IR spectra, which in combination with density functional theory (DFT) allow us to determine the conformational structures of the peptides. Molecular dynamics modeling using simulated annealing generates a variety of low-energy structures, for which geometry optimization and frequency calculations are then performed using the B3LYP functional with the 6-311+G(d,p) basis set. By comparing experimental and theoretical IR spectra, three conformations for Z-Glu-OH and two for Z-Arg-OH have been identified. For three of the five structures, the dispersion interaction provides an important contribution to the stabilization, emphasizing the importance of these forces in small peptides. Therefore, dispersion-corrected DFT functionals (M05-2X and B97D) have also been employed in our theoretical analysis. Second-order Møller-Plesset perturbation theory (MP2) has been used as benchmark for the relative energies of the different conformational structures. Finally, we address the ongoing debate on the gas-phase structure of arginine by elucidating whether isolated arginine is canonical, tautomeric, or zwitterionic.

Physicochemical characterization of a low-molecular-weight fructooligosaccharide from Chinese Cangshan garlic (Allium sativum L.).

A novel low-molecular-weight fructooligosaccharide (LMWF) from garlic ( Allium sativum ) was isolated and identified. The structure and physicochemical properties of the LMWF were determined by chemical and spectroscopic methods, size-exclusion chromatography, atomic force microscopy (AFM), dynamic rheometry, and differential scanning calorimetry (DSC). The results showed that the LMWF was a neo-ketose with a molecular weight of 1770 Da. The LMWF had a (2,1)-linked ß-D-Fruf backbone with (2,6)-linked ß-D-Fruf side chains, and it was mainly composed of fructose. The branch degree was 18.1%, and the intrinsic viscosity was 3.06 mL/g. The spherical particles of the LMWF were observed by AFM, and their size was relatively uniform. With an increase in the water content, the peak temperature (T(p)), onset temperature (T(o)), and endset temperature (T(c)) increased, while the gelatinization enthalpy (ΔH(gel)) decreased. The LMWF was more stable at a water content of 10%.

Multiple state transition interface sampling of alanine dipeptide in explicit solvent.

We have applied the recently developed multiple state transition interface sampling approach to alanine dipeptide in explicit water. We extract the rate constant matrix for configurational changes between each pair of metastable states. The results are comparable with values from previous literature and show that the method is applicable to biomolecular systems.

[Study on the expression and the role of macrophage migration inhibitory factor in the brain of neonatal rats with hypoxia-ischemia brain damage].

OBJECTIVE: To explore the expression of macrophage migration inhibitory factor (MIF), phosphorylated extracellular signal regulated kinases 1/2 (pERK1/2), matrix metalloproteinase-9 (MMP-9) in brain and the correlations with cerebral edema after hypoxia-ischemia brain damage (HIBD). METHODS: 144 seven-day-old SD rats were randomly dividend into three groups that was the sham operation group, HIBD group and intervention group with anti-MIF. Each group were executed in 1 h, 6 h, 12 h and 24 h, 3 d, and 7 d. The expression of MIF, MMP-9 protein in the right cerebral cortex was detected with immunohistochemistry methods, the relative content of pERK1/2 was detected with Western blot and the water content of brain was evaluated with dry-wet method. RESULTS: Comparing with the sham group the expression of MIF in the HIBD group began to increase on 1 h, and peaked on 24 h (P < 0.05), and MMP-9 began to express on 6 h, and also peaked on 24 h (P < 0.05), while pERK1/2 expressed rapidly to peak on 1 h, and quickly decreased on 6 h, and began to increase on 12 h and reached the peak again on 24 h (P < 0.05). Being treated with hypoxia-ischemia, the water content of brain began to increase on 6 h and peaked on 3 d (P < 0.05). And comparing with HIBD group, the expressions of MIF, pERK1/2, MMP-9 and the water contents were decreased obviously in the anti-MIF group (P < 0.05). CONCLUSION: The increased expression of MIF in the neonatal rats with hypoxia-ischemia brain damage maybe via activing the ERK1/2 ways to induce MMP-9 expressand leading to cerebral edema.

The photodissociation mechanisms of acrylonitrile: Ab initio calculations on reaction channels and surface intersections.

The dissociations of CH(2)CHCN into CH(2)CH+CN and CH(2)C+HCN in the S(0), T(1), and (1)pi(2)pi(C[triple bond]N) ( *) (definitions of pi orbitals can refer to computational details) states, have been explored at the complete active space self-consistent field level of theory employing the Dunning correlation consistent triple-zeta basis set. The lowest energy points of the surface crossing seams have been searched. Two conical intersections, from (1)pi(C[triple bond]N)pi(1) ( *) to (1)pi(2)pi(1) ( *) (CI(1)) and from (1)pi(2)pi(1) ( *) to S(0) (CI(2)), and one intersystem crossing point (T(1)/S(0)) have been located. The energies of all critical points have been recomputed with the multiconfigurational second-order perturbation method. At each conical intersection, derivative coupling and unscaled gradient difference vectors have been analyzed to determine the relaxation channels that the molecule may evolve in after nonradiative decay. Once the molecule is photoexcited to the (1)pi(2)pi(1) ( *) or (1)pi(C[triple bond]N)pi(1) ( *) state, it would relax along the similar pathway: funneling through CI(1) and then CI(2), and finally populate the ground state. Our results show that upon 193 nm photoexcitation, the most probable reaction channel is the ground-state HCN elimination following radiationless decays from excited states through surface crossings, which consists with experimental results J. Chem. Phys. 108, 5784 (1998). The investigated dissociation channels on the (1)pi(2)pi(C[triple bond]N) ( *) surface, which are inaccessible upon 193 nm photoexcitation, may provide information for reactions induced by higher energy excitations.